Bisaryl compound and medicament for cancer treatment comprising the same

ABSTRACT

A medicament for treatment of cancer comprising a compound represented by the following general formula (I) or a physiologically acceptable salt thereof: 
     
       
         Ar 1 —S—R 1 —S—Ar 2    
       
     
     wherein R 1  represents a nonmetal bridging group; Ar 1  and Ar 2  independently represent a group selected from the group consisting of an aryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group and said aryl group may have one to three substituents other than hydroxyl group on its ring; and a heteroaryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group, and said heteroaryl group may have one to three substituents other than hydroxyl group on its ring.

This application is a 371 of PCT/JP98/02242, filed May 21, 1998.

TECHNICAL FIELD

The present invention relates to a novel bisaryl compound and amedicament for treatment of cancer which comprises said compound or aknown bisaryl compound as an active ingredient.

BACKGROUND ART

In the cell proliferation process, DNA replication process is regulatedby a family of enzymes relating to nucleic acid synthesis. Among theseenzymes, it has been reported that ribonucleotide reductase(occasionally referred to as “RNR” hereinafter in this specification) isa particularly important enzyme involved in the biosynthesis of dNTPs,which are precursors of DNA (Ann. Rev. Biochem, 57, pp.349-374).

In cancer cells, endless cell proliferation continues due toover-expression of certain families of enzymes and the like, which leadsto death of the host. It has been reported that RNR is over-expressed incancer cells to maintain high ability of cell proliferation of cancercells (Cancer Research, 43, pp.3466-3492). Moreover, there has also beenreported a possibility that malignant alteration of cancer is causedwith accompanying expression of RNR (Proc. Natl. Acad. Sci. USA, 93,pp.14036-14040). Therefore, an agent selectively inhibiting RNR isexpected to be able to exert highly selective toxicity to cancer cells,and accordingly, expected to be useful as a medicament for cancertreatment that selectively inhibits the proliferation of cancer cells.

Hydroxyurea has been known as a compound exhibiting antitumor activityby inhibiting RNR, and the compound is used clinically as ananti-leukemia agent. However, the drug only has weak inhibitoryactivity, and therefore a high blood concentration need to be maintainedfor a long period of time to successfully inhibit RNR. In addition, thedrug causes strong side effects such as bone marrow toxicity, and henceis not a satisfactory therapeutic agent. For these reasons, it has beendesired to develop an RNR inhibitor which has potent RNR inhibitoryactivity as well as reduced side effects including bone marrow toxicity,and has a wide range of effective dosage.

As low molecular RNR inhibitors, there have so far been reportedpolyhydroxybenzoic acid derivatives (Published Japanese translation ofPCT international publication (Kohyo) No. 60-501409/1985), alkoxyphenolcompounds (Mol. Pharmacol., 45, pp.792-796), thiosemicarbazonederivatives (Biochem. Pharmacol., 48, pp.335-344), bipyridyl derivatives(Cancer Research, 53, pp.19-26) and the like. However, RNR inhibitoryactivity and anticancer activity of bisaryl derivatives have not beenreported. As for usefulness of bisaryl compounds composed of aryl groupslinked by means of plural sulfur atoms as anticancer agents, derivativescomprising aromatic benzenesulfonamide groups as the bisaryl moieties(Japanese Patent Publication (Kokoku) No. 42-10857/1967) have beenreported, and the synthesis of an anthramycin dimer has also beenreported (Tetrahedron Lett., 129, p.5105). It has also been known thatcertain bisaryl compounds have antiviral activity (Japanese PatentUnexamined Publication (Kokai) No. 5-501860/1993).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a novel bisphenolcompound useful as an active ingredient of a medicament.

Another object of the present invention is to provide an medicament fortreatment of cancer which comprises a bisphenol compound havinginhibitory activity against RNR as an active ingredient.

A still further object of the present invention is to provide a novelbisaryl compound useful as an active ingredient of a medicament.

The inventors of the present invention found that the compounds of thepresent invention represented by the following formula have inhibitoryactivity against RNR and anticancer activity, and thus they are usefulas an active ingredient of a medicament for treatment of cancer. Thepresent invention was achieved on the basis of these findings.

The present invention provides a medicament for treatment of cancerwhich comprises a compound represented by the following general formula(I):

Ar¹—S—R¹—S—Ar²

or a physiologically acceptable salt thereof,

wherein R¹ represents a nonmetal bridging group, Ar¹ and Ar²independently represent a group selected from the group consisting of anaryl group which has, on its ring, one or more hydroxyl groupsoptionally substituted with a monovalent group (the aryl group may haveone to three substituents other than a hydroxyl group on its ring), anda heteroaryl group which has, on its ring, one or more hydroxyl groupsoptionally substituted with a monovalent group (the heteroaryl group mayhave one to three substituents other than a hydroxyl group on its ring).

Preferred embodiments of the aforementioned invention provided are asfollows:

the above medicament for treatment of cancer which comprises a compoundrepresented by the aforementioned general formula (I) or aphysiologically acceptable salt thereof, wherein R¹ is represented bythe general formula (II):

—R²—N(R⁴)—R³—  (II)

wherein R² and R³ independently represent a divalent group, R⁴represents a monovalent group, and R⁴ may bind to R² or R³ to form acyclic structure; the above medicament for treatment of cancer whichcomprises the aforementioned compound or a physiologically acceptablesalt thereof, wherein R¹ is represented by the general formula (III):

—R⁵—X¹—R⁶—  (III)

wherein R⁵ and R⁶ independently represent a single bond or a divalentgroup not containing a nitrogen atom, X¹ represents an oxygen atom,S(O)_(k) wherein k represents an integer of from 0 to 2, or[(R⁹X²)_(m)(R¹⁰X³)_(n)(R¹¹X⁴)_(p)]_(q) wherein R⁹, R¹⁰, and R¹¹independently represent a single bond or a divalent group not containinga nitrogen atom, and wherein any groups selected from R⁵, R⁶, R⁹, R¹⁰and R¹¹ may bind together to form a cyclic structure, X², X³ and X⁴independently represent an oxygen atom, S(O)_(r) wherein r represents aninteger of from 0 to 2, or a single bond, and m, n, p and qindependently represent an integer of from 1 to 3;

the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R¹ is 2,6-pyridinediyldimethyl group (the pyridinediyldimethylgroup may have one to three substituents other than a hydrogen atom onits ring);

the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same divalent groups, and R⁴ is a C₁₋₄ alkylgroup which may have one to three substituents other than a hydrogenatom;

the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same divalent groups, R⁴ is represented asCOR²⁵ wherein R²⁵ represents a hydrogen atom, a C₁₋₄ alkyl group, anaryl group, a heteroaryl group, a heterocyclic group, an aralkyl group,or NR²⁶R²⁷ wherein R²⁶ and R²⁷ each represent a hydrogen atom, a C₁₋₄alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, oran aralkyl group, and said alkyl group, aryl group, heteroaryl group,heterocyclic group, and aralkyl group including those for R²⁶ and R²⁷may have one to three substituents other than a hydrogen atom; and

the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R¹ is represented asR^(1A)—R^(1B)CO—R^(1C)—R^(1D)—R^(1C)—COR^(1B)—R^(1A) wherein R^(1A)represents a C₁₋₄ lower alkylene group, R^(1B) represents NH or amethylene group, R^(1C) represents a single bond or a methylene group,R^(1D) represent a divalent bridging cyclic hydrocarbon group, amonocyclic hydrocarbon group, or a heterocyclic group, and said bridgingcyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclicgroup may have one to three substituents other than a hydrogen atom.

According to further preferred embodiments of the aforementioned eachinvention provided are the above medicament for treatment of cancerwhich comprises the aforementioned compound or a physiologicallyacceptable salt thereof, wherein Ar¹ and Ar² independently represent theaforementioned aryl group; the above medicament for treatment of cancerwhich comprises the aforementioned compound or a physiologicallyacceptable salt thereof, wherein both of Ar¹ and Ar² are 4-hydroxyphenylgroups; the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same groups, and the minimum number ofbridge-forming atoms thereof is from 1 to 10, preferably 1 to 4; theabove medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein R² and R³ are the same divalent groups optionally having abranched chain (said divalent groups may contain 1 to 3 oxygen atoms);the above medicament for treatment of cancer which comprises theaforementioned compound or a physiologically acceptable salt thereof,wherein the total number of carbon atoms is 35 or less; and the abovemedicament for treatment of cancer which comprises the aforementionedcompound or a physiologically acceptable salt thereof, which is used asa medicament for preventive and/or therapeutic treatment of a diseasecaused by over-expression of ribonucleotide reductase.

As another aspect of the present invention, provided is a ribonucleotidereductase inhibitor or a selective cancer cell proliferation inhibitorwhich comprises a compound represented by the aforementioned generalformula (I) or (II).

As further aspects of the present invention, provided are use of theaforementioned compound or a physiologically acceptable salt thereof forthe manufacture of the medicaments for treatment of cancer whichcomprise a compound represented by the aforementioned general formula(I) or (II), or a physiologically acceptable salt thereof as an activeingredient, preferably the medicaments for treatment of cancer in theform of a pharmaceutical composition comprising the aforementionedcompound or a physiologically acceptable salt thereof together with anadditive for pharmaceutical preparations; and a method for treatment ofcancer which comprises the step of administering a therapeuticallyeffective amount of a substance selected form the aforementionedcompound and a physiologically acceptable salt thereof to a patient.

The present invention further provides a compound represented by thegeneral formula (XII):

Ar²³—S—R²²—N(R²⁴)—R²³—S—Ar²⁴

or a salt thereof,

wherein, R²² and R²³ independently represent a divalent group, R²⁴represents a monovalent group or a monovalent atom, and R²⁴ may bind toR²² and/or R²³ to form a cyclic structure, and may further bind to oneor two C₁₋₄ alkylene groups to form a divalent group, and Ar²³ and Ar²⁴independently represent a group selected from the group consisting of anaryl group which has, on its ring, one to three hydroxyl groupsoptionally substituted with a monovalent group (the aryl group may haveone to three substituents other than a hydroxyl group on its ring), anda heteroaryl group which has, on its ring, one to three hydroxyl groupsoptionally substituted with a monovalent group (the heteroaryl group mayhave one to three substituents other than a hydroxyl group on its ring),provided that R²²—N(R²⁴)—R²³ except for the part of R²⁴ does not containan amide bond when R²² and R²³ do not form a ring, and provided thatwhen each of Ar²³ and Ar²⁴ is a phenyl group having one hydroxyl groupon the ring, not all of said phenyl groups have a tertiary alkyl groupat a position on the ring adjacent to the hydroxyl group.

As a preferred embodiment of the above invention, provided is theaforementioned compound or a salt thereof, wherein two or three groupsselected from the group consisting of R²², R²³ and R²⁴ form a ring orrings.

Further preferred embodiments provided are as follows:

the above compound or a salt thereof wherein R²² and R²³ are the samedivalent groups, and R²⁴ is a C₁-4 alkyl group which may have one tothree substituents other than a hydrogen atom;

the above compound or a salt thereof wherein R²² and R²³ are the samedivalent groups, R²⁴ is represented by COR¹²⁵ wherein R¹²⁵ represents ahydrogen atom, a C₁₋₄ alkyl group, an aryl group, a heteroaryl group, aheterocyclic group, an aralkyl group, or NR¹²⁶R¹²⁷ wherein R¹²⁶ and R¹²⁷each represent a hydrogen atom, a C₁₋₄ alkyl group, an aryl group, aheteroaryl group, a heterocyclic group, or an aralkyl group, and saidalkyl group, aryl group, heteroaryl group, heterocyclic group, andaralkyl group including those for R¹²⁶ and R¹²⁷ may have one to threesubstituents other than a hydrogen atom; and

the above compound or a salt thereof wherein R²²—N(R²⁴)—R²³ isrepresented byR^(101A)—R^(101B)CO—R^(101C)—R^(101D)—R^(101C)—COR^(101B)—R^(101A)wherein R^(101A) represents a C₁₋₄ lower alkylene group, R^(101B)represents NH or methylene group, R^(101C) represents a single bond or amethylene group, R^(101D) represent a divalent bridging cyclichydrocarbon group, a monocyclic hydrocarbon group, or a heterocyclicgroup, and said bridging cyclic hydrocarbon group, monocyclichydrocarbon group, and heterocyclic group may have one to threesubstituents other than a hydrogen atom.

Further preferred embodiments provided are as follows:

the above compound or a salt thereof wherein Ar²³ and Ar²⁴ independentlyrepresents an aryl group which has, on its ring, one to three hydroxylgroups optionally substituted with a monovalent group (the aryl groupmay have one to three substituents other than a hydroxyl group on itsring);

the above compound or a salt thereof wherein both of Ar²³ and Ar²⁴independently represent a hydroxy-substituted phenyl group;

the above compound or a salt thereof wherein Ar²³ and Ar²⁴ independentlyrepresent a monohydroxy-substituted phenyl group;

the above compound or a salt thereof wherein both of Ar²³ and Ar²⁴ are4-hydroxyphenyl groups;

the above compound or a salt thereof wherein the minimum number ofbridge-forming atoms of R²² and R²³ are independently from 1 to 10 [Theterm “minimum number of bridge-forming atoms” used herein means aminimum number of atoms that connect one atom and the other atom to bebridged. For example, the minimum number of bridge-forming atoms is 3for 1,3-propenylene group, 2 for 1,2-propenylene group, and 5 for1,5-(4-butoxy-3-pentenylene) group. Also for example, the number is 3for 1,3-phenylene group, 2 for 1,2-phenylene group, 3 for2,4-quinolinediyl group, and 4 for 1,5-naphthylene, as well as 4 forethylenedioxy group, 3 for malonyl group, and 4 for phthaloyl group.];

the above compound or a salt thereof wherein R²² and R²³ are the samegroups and each of the minimum numbers of bridge-forming atoms thereofis 1 to 10, preferably 1 to 4;

the above compound or a salt thereof wherein R²² and R²³ independentlyrepresent methylene group, ethylene group, propylene group or butylenegroup;

the above compound or a salt thereof wherein R²² and R²³ are the samegroups, and represent methylene group, ethylene group, propylene groupor butylene group; and

the above compound or a salt thereof wherein the total number of carbonatoms is 35 or less.

BEST MODE FOR CARRYING OUT THE INVENTION

The groups that constitute the general formulas (I) and (II) will beexplained specifically.

The aryl group represented by Ar¹ and Ar² in the general formula (I) maybe, for example, an aryl group having 6 to 12 carbon atoms, preferablyphenyl group, naphthyl group or the like. The term “aryl group” has thesame meaning in the following description unless otherwise indicated.The heteroaryl group may be, for example, a heteroaryl group having 5 to12 ring-constituting atoms, such as pyridyl group, pyrrolyl group,imidazolyl group, quinolinyl group, thienyl group, and furyl group. Asthe heteroaryl group, for example, a group comprising a 5- or 6-memberednitrogen-containing or oxygen-containing heteroaryl ring having an enoltype hydroxyl group and an active methine or active methylene group,such as pyrazolone ring and pyridone ring, may preferably used. The term“heteroaryl group” has the same meaning in the following descriptionunless otherwise indicated. It is preferred that both of Ar¹ and Ar² arearyl groups, and it is more preferred that both of Ar¹ and Ar² arephenyl groups.

The number and the substituting position of the hydroxyl group or thehydroxyl group substituted with a monovalent group on the ring of thearyl group or the heteroaryl group are not particularly limited, andthey preferably have one hydroxyl group. For example, when the arylgroup is phenyl group, phenyl group substituted with one hydroxyl groupat the p-position (4-position) may be exemplified. Examples of themonovalent group in the one to three hydroxyl groups substituted with amonovalent group present independently on the ring of the aryl group orthe heteroaryl group include, but not limited thereto, linear orbranched C₁₋₆ alkyl groups such as methyl group, ethyl group, n-propylgroup, isopropyl group, n-butyl group, sec-butyl group and tert-butylgroup; aryl groups such as phenyl group and naphthyl group; C₁₋₁₂alkanoyl groups which may be substituted; hydroxy(C₂₋₆)alkyl groups suchas hydroxyethyl group; C₇₋₁₅ aralkyl groups such as benzyl group andphenethyl group; C₆₋₁₂ aroyl groups; C₁₋₆ alkylsulfonyl groups; C₆₋₁₂arylsulfonyl groups; C₁₋₆ alkoxycarbonyl groups; aryloxycarbonyl groups;hydroxyphenylthio(C₁₋₆) alkyl groups; aminocarbonyl groups substitutedwith 0 to two C₁₋₆ alkyl groups or C₆₋₁₂ aryl groups; aminoalkylcarbonylgroups substituted with 0 to two C₁₋₆ alkyl groups or C₆₋₁₂ aryl groups;C₁₋₆ alkoxy-substituted C₁₋₆ alkanoyl groups, C₁₋₆alkylamino-substituted C₁₋₆ alkanoyl groups, piperidinocarbonyl group,4-piperidinopiperidinocarbonyl group, N-t-butoxycarbonyl-N-methylglycylgroup and the like.

On the ring of the aforementioned aryl group or the heteroaryl group,one to three substituents other than a hydroxyl group or a hydroxylgroup substituted with a monovalent group may be present. As such asubstituent, examples which can be used are as follows: a halogen atomselected from fluorine atom, chlorine atom, bromine atom, and iodineatom; a C₁₋₆ alkyl group such as methyl group, ethyl group, n-propylgroup, isopropyl group, n-butyl group, sec-butyl group and tert-butylgroup; a halogenated C₁₋₆ alkyl group such as trifluoromethyl group; aC₁₋₆ alkoxyl group such as methoxy group, ethoxy group, n-propoxy group,isopropoxy group, n-butoxy group, sec-butoxy group and tert-butoxygroup; a C₁₋₆ alkylenedioxy group such as methylenedioxy group andethylenedioxy group; carboxyl group; a C₁₋₆ alkoxycarbonyl group;non-substituted amino group; a C₁₋₆ alkyl-substituted amino group suchas methylamino group, dimethylamino group and ethylamino group; cyanogroup or the like. Among them, halogen atoms, C₁₋₆ alkyl groups, C₁₋₆alkoxyl groups and the like are preferred.

In the specification, the term “bridging group” means a group or an atomthat can form two independent covalent bonds. In the specification, theterm “divalent group” means the bridging group which can form twoindependent covalent bonds, and contains at least one carbon atom. Thedivalent group may have a chain-like or a cyclic structure, or may havea combination of portions of a chain-like structure and a cyclicstructure.

R¹ in the general formula (I) represents a divalent group consisting ofa nonmetal bridging group, which preferably comprising atoms selectedfrom the group consisting of carbon atom, hydrogen atom, oxygen atom,nitrogen atom, sulfur atom, and phosphorus atom, and has atoms excludinghydrogen the number of which is 1 to 80. R¹ may further contain one tothree halogen atoms.

These divalent groups may contain one to three unsaturated bonds, suchas a double bond consisting of a carbon-carbon bond, carbon-oxygen bond,sulfur-oxygen bond, carbon-nitrogen bond, or nitrogen-nitrogen bond, ortriple bond consisting of a carbon-carbon bond. Furthermore, they maycontain one to three covalent bonds including any hetero atoms such ascarbamoyl bond, sulfamoyl bond, ether bond, and disulfide bond as apartial structure. For example, they may contain one to three cyclicstructures selected from monocyclic structures such as those consistingof benzene ring, cyclohexane ring, tetrahydrofuran ring, and pyranonering, condensed rings such as naphthalene ring, indole ring, andquinoline ring, and bicyclo structures such as bicyclooctane ring.Furthermore, examples also include pyrrole ring, piperidine ring, indolering, pyridine ring, triazine ring, pyrimidine ring, quinoline ring,oxazine ring, indazole ring, thiazole ring and the like. When thedivalent group is a cyclic group or chain-like group, or when itcontains a partial chain-like structure, it may contain a branchedchain.

The aforementioned ring that constitutes the divalent group, and carbonatoms and/or hetero atoms constituting the backbone of the divalentgroup may have one or more substituents thereon, for example, thoseselected from the group consisting of a halogen atom such as fluorineatom, chlorine atom, and bromine atom; a linear or branched C₁₋₆ alkylgroup such as methyl group, ethyl group, n-propyl group, isopropylgroup, n-butyl group, sec-butyl group, and tert-butyl group; a linear orbranched C₁₋₆ alkoxyl group such as methoxy group, ethoxy group,n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group andtert-butoxy group (those alkyl and alkoxyl groups may have a substituentsuch as hydroxyl group, a C₁₋₆ alkoxyl group, a C₁₋₆ alkyl-substitutedor non-substituted carbamoyl group, non-substituted amino group, a C₁₋₆alkyl-substituted amino group such as methylamino group, dimethylaminogroup, and ethylamino group, a C₁₋₆ cyclic amino group such asmorpholino group and piperidino group, and a C₁₋₆ cyclic aminocarbonylgroup such as morpholino group and piperidino group); a C₁₋₆alkylenedioxy group such as methylenedioxy group and ethylenedioxygroup; carboxyl group; a C₁₋₆ alkoxycarbonyl group; non-substitutedamino group or a C₁₋₆ alkyl-substituted amino group such as methylaminogroup, dimethylamino group and ethylamino group; hydroxyl group; an arylgroup such as phenyl group; a C₁₋₆ alkyl-substituted sulfonyl group; aC₁₋₆ alkanoyl group such as acetyl group and propionyl group; ahalogenated C₁₋₆ alkanoyl group such as trifluoroacetyl group andmonochloroacetyl group; an alkoxy-substituted C₁₋₆ alkanoyl group suchas methoxymethylcarbonyl group; cyano group; a C₁₋₆ alkyl-substituted ornon-substituted carbamoyl group; sulfamoyl group; carboxyl group; sulfogroup; a lactone ring or a lactam ring consisting of 4 to 8ring-constituting atoms; and a halogen atom.

Preferred examples of the divalent group represented by R¹ include, forexample, linear or branched C₁₋₆ alkylene groups such as methylenegroup, ethylene group, propylene group, butylene group, and pentylenegroup; arylene groups such as p-phenylene group, m-phenylene group,1,4-naphthylene group, and 1,5-naphthylene group; heteroarylene groupssuch as 2,6-pyridinediyl group; vinylene group; ethynylene group;propenylene group; propynylene group; C₂₋₆ alkenylene groups such as1-butenylene group, and cis- and trans-2-butenylene group, C₂₋₆alkynylene groups and the like. These divalent groups may have one tothree substituents selected from the aforementioned substituents.Preferred examples of the alkylene group having one or more substituentsinclude, for example, oxo(C₁₋₆)alkylene groups such as 1-oxoethylenegroup, 1-oxo-2-methylethylene group, and 1-oxopropylene group; andoxy(C₁₋₆)alkylene groups such as 1-oxypropylene group, and2-oxypropylene group and the like. Divalent groups consisting of asuitable combination of groups selected from alkylene groups, arylenegroups and heteroarylene groups are also preferred.

Those wherein R¹ representsR^(1A)—R^(1B)CO—R^(1C)—R^(1D)—R^(1C)—COR^(1B)R^(1A), wherein R^(1A)represents a C₁₋₄ lower alkylene group, R^(1B) represents NH or amethylene group, R^(1C) represents a single bond or a methylene group,R^(1D) represents a divalent bridging cyclic hydrocarbon group, amonocyclic hydrocarbon group, or a heterocyclic group, and said bridgingcyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclicgroup may have one to three substituents other than a hydrogen atom, arealso preferred examples of the divalent group. Examples of the divalentbridging cyclic hydrocarbon group and monocyclic hydrocarbon groupinclude, for example, 1,1-cyclopentylene, 5,6-norbornenylene,1,1-cyclopropylene, 1,1-cyclobutylene, 1,2-cyclobutylene,1,2-cyclopentylene, 2,2-dimethyl-1,3-cyclopentylene, 1,1-cyclohexylene,1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene,1,3-adamantylene, 1,1-phenylene, 1,2-phenylene, 1,3-phenylene,1,4-phenylene, 1,4-naphthylene, 2,3-naphthylene, 2,6-naphthylene,1,8-naphthylene and the like. Examples of the divalent heterocyclicgroup include, for example, 1,4-piperazinylene, 4-oxo-2,6-pyranylene,2,3-pyrrolylene, 3,5-pyrazolylene, 2,3-indolylene, 2,6-pyridylene,2,3-pyridylene, 2,4-pyridylene, 3,4-pyridylene, 2,5-pyridylene,3,5-pyridylene, 2,3-pyrazinylene, 3,4-furylene, 4,5-imidazolylene,1,2,3-triazol-4, 5-ylene, 7-oxabicyclo[2.2.1]heptynyl-2,3-ylene,tricyclo[4.2.1.0^(2.5)]nona-3,7-dien-3,4-ylene,2,2-dimethyldioxolan-4,5-ylene and the like. As preferred substituentson the divalent bridging cyclic hydrocarbon group, monocyclichydrocarbon group, and heterocyclic group, those exemplified for thesubstituents on the rings of the aforementioned aryl group andheteroaryl group may be used.

The minimum number of bridging group-forming atoms of R¹ is preferablyin the range of 1 to 20, more preferably 1 to 9, and most preferably 3to 7. The total atom number of the whole compound of the general formula(I) is preferably 50 or less.

The groups that constitute the compounds represented by the generalformula (II) will be specifically explained below.

The definition of the divalent group represented by R² and R³ is thesame as that of the divalent group represented by R¹ in the generalformula (I), provided that particularly preferred minimum number ofbridge-forming atoms of R² and R³ is in a range of from 1 to 3.

In the formula (II), R⁴ represents a monovalent group or a monovalentatom. R⁴ may be, for example, a hydrogen atom, hydroxyl group, amidinogroup, amino group, an alkyl group which may be substituted, an arylgroup which may be substituted, a heteroaryl group which may besubstituted, an aralkyl group which may be substituted, an alkyl groupsubstituted with a heteroaryl group which may be substituted, or a grouprepresented by any one of the following formulas (XIII) to (XVI):

—CO—R²⁵  (XIII)

wherein R²⁵ represents a hydrogen atom, a C₁₋₄ alkyl group which may besubstituted, an aryl group which may be substituted, a heteroaryl groupwhich may be substituted, a heterocyclic group which may be substituted,or an aralkyl group which may be substituted;

—CO—NR²⁶R²⁷  (XIV)

wherein R²⁶ and R²⁷ independently represent a hydrogen atom, a C₁₋₄alkyl group which may be substituted, an aryl group which may besubstituted, a heteroaryl group which may be substituted, a heterocyclicgroup which may be substituted, or an aralkyl group which may besubstituted;

—SO₂—R²⁵  (XV)

wherein R²⁵ has the same meaning as that defined above; and

—SO₂—NR²⁶R²⁷  (XVI)

wherein R²⁶ and R²⁷ have the same meanings as those defined above.

Where R⁴ is an alkyl group which may be substituted, the alkyl group maybe linear or branched, and it may contain one or more cyclic structuresor one or more unsaturated bonds. The number of carbon atoms thereof maypreferably be 20 or less including its substituent(s). Particularlypreferred group may contain 1 to 4 carbon atoms. Preferred examples ofthe substituent include, but not limited thereto, halogen atoms such asfluorine atom, chlorine atom, bromine atom, and iodine atom, hydroxylgroup, carboxyl group, vinyl group, ethynyl group, C₃₋₈ cycloalkylgroups, carbamoyl group which may have a substituent on the nitrogenatom (one or two substituents selected from a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a hydroxy-substituted C₁₋₆ alkyl group, anaryl group, a sulfonyl group, a C₁₋₆ alkyl-substituted sulfonyl group, aC₁₋₆ alkanoyl group, a halogenated C₁₋₆ alkanoyl group, ahydroxy-substituted C₁₋₆ alkanoyl group, an alkoxy-substituted C₁₋₆alkanoyl group and the like), a sulfamoyl group which may have asubstituent on the nitrogen atom (one or two substituents selected fromthose exemplified for the aforementioned carbamoyl group), C₁₋₂₀alkanoyl groups, aroyl groups, heteroarylcarbonyl groups, C₁₋₂₀alkanoylamino groups, aroylamino groups, heteroarylcarbonylamino groups,C₁₋₂₀ alkylsulfonyl groups, arylsulfonyl groups, heteroarysulfonylgroups, C₁₋₂₀ alkylsulfonylamino groups, arylsulfonylamino groups,heteroarylsulfonylamino groups, an ureido group which may have asubstituent on the nitrogen atom (one or two substituents selected fromthose exemplified for the aforementioned carbamoyl group), a cyanogroup, an amino group which may have a substituent on the nitrogen atom(one or two substituents selected from those exemplified for theaforementioned carbamoyl group), C₁₋₂₀ alkylthio groups, C₁₋₂₀ alkoxylgroups, aryloxy groups, heteroaryloxy groups, arylthio groups, arylthiogroups substituted with one to three hydroxyl groups, C₁₋₂₀alkoxycarbonyl groups, aryloxycarbonyl groups, heteroaryloxycarbonylgroups, a 2-hydroxyethoxy group, polyether groups (2-methoxyethoxygroup, 2-(2-methoxyethoxy)ethoxy group etc.), a succinimido group, aguanidino group, aryl groups, aryl groups which are substituted with oneor two hydroxyl groups, aryl groups which are substituted with 1 to 5independently selected halogen atoms (a halogen atom has the samemeaning as that defined above), heteroaryl groups, heterocyclic groupsand the like.

The aryl group of the aforementioned aryl group, aroyl group, aroylaminogroup, arylsulfonyl group, arylsulfonylamino group, aryloxy group, andaryloxycarbonyl group, and the heteroaryl group of the aforementionedheteroaryl group, heteroarylcarbonyl group, heteroarylsulfonyl group,heteroarylsulfonylamino group, heteroaryloxy group, andheteroaryloxycarbonyl group have the same meanings as those definedabove. Examples of the heterocyclic group include, for example,dioxolanyl group, morpholino group, morpholyl group, piperidyl group,dioxanyl group, imidazolyl group, thiazolyl group, pyrimidinyl group,2,2-dimethyl-1,3-dioxolanyl group and the like.

Preferred examples of R⁴ include, but not limited thereto, methyl group,ethyl group, propyl group, sec-butyl group, cyclopropylmethyl group,allyl group, propargyl group, 2-fluoroethyl group, 2,2,2-trifluoroethylgroup, 2-hydroxyethyl group, 3-hydroxypropyl group, carbamoylmethylgroup, 2-carbamoylethyl group, 2-(N,N-dimethylcarbamoyl)ethyl group,2-(N-morpholinocarbonyl)ethyl group, 2-(N-piperidinocarbonyl)ethylgroup, sulfamoylmethyl group, acetylmethyl group, 2-(N-acetylamino)ethylgroup, cyanomethyl group, 2-(N,N-diethylamino)ethyl group,2-(N-morpholino)ethyl group, 2-(N-piperidino)ethyl group,2-methylthioethyl group, 2-methoxyethyl group, hydroxyethoxyethyl group,methoxycarbonylmethyl group and the like.

When R⁴ is an aryl group which may be substituted, the number of carbonatom is preferably 20 or less including its substituent(s). Preferredexamples include, for example, phenyl group which may be substituted andnaphthyl group which may be substituted. When these groups have asubstituent, they may have one to three substituents. Preferred examplesof the substituent are those exemplified as preferred substituents forR⁴ when it represents the alkyl group. Among them, halogen atoms,hydroxyl group, carbamoyl group and the like are particularly preferred.When R⁴ is a heteroaryl group which may be substituted, the number ofcarbon atoms is preferably 20 or less including its substituent(s).Preferred examples include, for example, pyridyl group, thienyl group,furyl group, imidazolyl group, quinolyl group and the like. These groupsmay have one to three substituents selected from those exemplified aspreferred substituents for R⁴ when it represents the alkyl group.

Where R⁴ is an aralkyl group which may be substituted or an alkyl groupsubstituted with a heteroaryl group which may be substituted, the numberof carbon atoms thereof is preferably 20 or less including theirsubstituent(s). Preferred examples include, for example, benzyl group,2-phenylethyl group, naphthylmethyl group, 2-picolyl group, 3-picolylgroup, (2-furyl)methyl group, (2-thienyl)methyl group,(2-quinolyl)methyl group, 2-(2-pyridyl)ethyl group,2-(N-imidazolyl)ethyl group and the like. These groups may have one tothree substituents selected from those exemplified as preferredsubstituents for R⁴ when it represents the alkyl group. Among them,halogen atoms, hydroxyl group, carbamoyl group and the like areparticularly preferred substituents.

Where R⁴ is a group represented by the formula (XIII) or the formula(XV), the group represented by R²⁵ preferably has 15 or less carbonatoms, and it may have one to three substituents selected from thoseexemplified as preferred substituents for R⁴ when it represents thealkyl group. The aryl group, heteroaryl group, heterocyclic group andaralkyl group for R²⁵ have the same meanings as those defined above.Preferred examples of R⁴ include, for example, acetyl group, propionylgroup, benzoyl group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group,4-pyridylcarbonyl group, benzylcarbonyl group, methanesulfonyl group,benzenesulfonyl group and the like.

Where R⁴ is a group represented by the formula (XIV) or the formula(XVI), those groups represented by R²⁶ and R²⁷ preferably have 15 orless carbon atoms, and they may have one to three substituents selectedfrom those exemplified as preferred substituents for R⁴ when itrepresents the alkyl group. In addition, R²⁶ and R²⁷ may bind to eachother to form a ring structure. Preferred examples of R⁴ include, forexample, aminocarbonyl group, N-methylaminocarbonyl group,N-phenylaminocarbonyl group, N-(2-pyridylamino)carbonyl group,N,N-dimethylaminocarbonyl group, N,N-diethylaminocarbonyl group,N-morpholinocarbonyl group, N-piperidinocarbonyl group, aminosulfonylgroup, N,N-dimethylaminosulfonyl group, N,N-diethylaminosulfonyl group,N-morpholinosulfonyl group, N-piperidinosulfonyl group and the like.

The ring structure which is formed by R⁴ together with R² or R³ includessaturated and unsaturated ring structures. Examples of the ring include,for example, saturated or unsaturated 3- to 18-membered monocyclic ringsor condensed rings, such as pyrrole ring, piperidine ring, indole ring,pyridine ring, triazine ring, pyrimidine ring, quinoline ring, oxazinering, indazole ring, and thiazole ring. These rings may be partially orfully reduced or oxidized. Furthermore, they may further bind to one ortwo C₁₋₄ alkylene groups to form a divalent group.

A compound in which one monovalent group such as an alkyl group furtherbind to a nitrogen atom in the general formula (II) to form a quaternarysalt of the nitrogen atom may also be used as an active ingredient ofthe medicament for treatment of cancer of the present invention. As acounter ion of the quaternary salt, for example, iodine ion, bromineion, chlorine ion, perchlorate ion, sulfate ion, phosphate ion,sulfamate ion, acetate ion, lactate ion, citrate ion, tartrate ion,malonate ion, methanesulfonate ion, ethanesulfonate ion,hydroxyethanesulfonate ion, benzenesulfonate ion, p-toluenesulfonateion, and cyclohexylsulfamate ion may be used. Iodine ion, bromine ion,chlorine ion, and perchlorate ion can be preferably used. As themonovalent group, C₁₋₆ alkyl groups such as methyl group are preferred.

Divalent groups preferred as R¹, R², and R³ in the general formula (I)and (II) will be exemplified blow. However, the divalent group which canbe used for the compound as the active ingredient of the medicament fortreatment of cancer of the present invention is not limited to theseexamples (in the structures, Me represents methyl group).

The bisaryl compounds represented by the aforementioned general formula(I) have inhibitory activity against ribonucleotide reductase, and canselectively inhibit cancer cell proliferation. Therefore, they can beused as an active ingredient of a medicament for treatment of cancer,which can be administered to mammals including human. Types of cancersto be treated by the medicament of the present invention are notparticularly limited, and the medicament can be applied to solid cancerssuch as stomach cancer, lung cancer, colon cancer, liver cancer, kidneycancer, breast cancer, uterus cancer, skin cancer and brain tumor, aswell as non-solid cancers such as leukemia and lymphoma.

In addition, they are also useful as an active ingredient of medicamentsfor preventive and/or therapeutic treatment of various diseases inmammals including human accompanied by unusual expression ofribonucleotide reductases deriving from host mammals themselves,viruses, bacteria and the like, for example, herpes syndrome caused byunusual proliferation of herpes simplex virus, acquired immunedeficiency syndrome caused by unusual proliferation of AIDS virus andthe like. Furthermore, the aforementioned compounds, per se, can also beused as ribonucleotide reductase inhibitors such as reagents in thefields of biochemistry, pharmacology, genetic engineering and the like.As the active ingredient of the medicament of the present invention, asubstance selected from the group consisting of the compounds of theaforementioned general formula (I) and salts thereof, and hydratesthereof and solvates thereof can be used, as well as any combinations oftwo or more of substances selected from said group.

Although the aforementioned substances, per se, may be used as themedicament of the present invention, it is generally preferred that themedicament is provided for administration as a pharmaceuticalcomposition that can be prepared by using one or more pharmaceuticallyacceptable additives. Administration route of the medicament of thepresent invention is not particularly limited, and oral or parenteraladministration may be selected. Examples of the pharmaceuticalcompositions suitable for parenteral administration include, forexample, injections suitable for intravenous, intraarterial,intraperitoneal or intrapleural injection, drip infusions, preparationsfor intrarectal administration (suppositories) and the like. Examples ofthe pharmaceutical compositions suitable for oral administrationinclude, for example, tablets, capsules, granules, powders, syrups andthe like. However, applicable pharmaceutical compositions are notlimited to these examples, and those skilled in the art can select asuitable form of composition from available pharmaceutical compositions.

For example, for the manufacture of injections, the aforementionedsubstances as an active ingredient may be dissolved in a diluentavailable to those skilled in the art (for example, physiologicalsaline, glucose solution for injection, lactose solution for injection,mannitol solution for injection and the like), and then the solution maybe subjected to an appropriate sterilization treatment such asfiltration sterilization, and filled in hermetic containers such asampoules. Preparation for injection in a lyophilized form or powder forinjection mixed with sodium chloride may also be prepared according tothe Japanese Pharmacopoeia. As the pharmaceutical additives, forexample, carriers such as auxiliaries such as polyethylene glycol andHCO-60 (surfactant; Nikko Chemical Co. Ltd.), ethanol and/or liposomeand cyclodextrin may be incorporated. Pharmaceutical compositionssuitable for oral administration or intrarectal administration can beprepared by mixing the aforementioned substances with appropriatepharmaceutical additives such as excipients, disintegrating agents,binders, lubricants, suspending agents, isotonic agents, and emulsifiersin a conventional manner, and formulating the mixture into anappropriate form.

Dosage and administration frequency of the medicament of the presentinvention are not particularly limited. When the medicament of thepresent invention is used for treatment of cancer, it can beadministered, for example, via intravenous route in an amount of 0.01 to100 mg/kg (based on the weight of the active ingredient) at intervals ofevery week to every 3 weeks. It is desirable to suitably adjust thedosage and administration frequency depending on various conditions, forexample, route of administration, a kind of an active ingredient, i.e.,the compound of the aforementioned formulas (I) to (III), the age andbody weight of patients, the condition, and frequency and severity ofside effects such as bone marrow suppression.

The bisaryl compounds represented by the aforementioned general formula(I) may have one to three asymmetric carbons depending on the kind ofthe substituents. Furthermore, a sulfur atom may also serve as anasymmetric center. Any optical isomers in an optically pure form basedon one to three asymmetric carbons, any mixtures of the aforementionedoptical isomers, and racemates, as well as diastereomers based on two ormore asymmetric carbons, any mixtures of such diastereomers and the likemay be used as the active ingredient of the medicament of the presentinvention. As the active ingredient of the medicament of the presentinvention, those in free form encompassed by the aforementioned formulaas well as physiologically acceptable salts thereof may be used.

Examples of such salts include, for example, hydrochlorides, sulfates,phosphates, sulfamates, acetates, lactates, citrates, tartrates,malonates, methanesulfonates, ethanesulfonates, hydroxyethanesulfonates,benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and thelike. These salts can be prepared by dissolving the aforementionedcompound as free base in water, an aqueous organic solvent such asalcoholic solvent or a suitable organic solvent containing acorresponding acid to form a uniform solution, and isolating a saltafter evaporation of water or the organic solvent, or allowing thecompound in free form to react with an acid in an organic solvent. Inthe latter case, for example, the resulting salt can be directlyisolated, or recovered by evaporation of the solvent. As the activeingredient of the medicament of the present invention, theaforementioned compounds in free form and salts thereof, and inaddition, hydrates thereof and solvates thereof can be used. Examples ofthe organic solvent for forming the solvates include, for example,physiologically acceptable solvents such as ethanol and ethylene glycol.

Specific examples of the compounds most suitably used for the medicamentof the present invention will be listed below. However, the activeingredient of the medicament of the present invention is not limited tothe following compounds (in the tables, the serial numbers in the firstleft column indicate the compound numbers, Ph represents phenyl group,and p-HO-Ph represents p-hydroxyphenyl group. In Table 3, “B” representsp-hydroxyphenylthio group, Me represents methyl group, Et representsethyl group, and Ac represents acetyl group).

TABLE 1 Compound No. 1

Compound No. 2

Compound No. 3

Compound No. 4

Compound No. 5

Compound No. 6

Compound No. 7

Compound No. 8

Compound No. Ar¹ R¹ Ar¹  9 p-HO—Ph— —C₂H₄—S—C₂H₄— p-HO—Ph— 10 p-HO—Ph——C₂H₄—S—C₃H₆— p-HO—Ph— 11 p-HO—Ph— —C₂H₄—S—C₄H₄— p-HO—Ph— 12 p-HO—Ph——C₂H₄—S—C₄H₆— p-HO—Ph— 13 p-HO—Ph— —C₂H₄—S—C₄H₈— p-HO—Ph— 14 p-HO—Ph——C₃H₆—S—C₃H₆— p-HO—Ph— 15 p-HO—Ph— —C₃H₆—S—C₄H₆— p-HO—Ph— 16 p-HO—Ph——C₃H₆—S—C₄H₈— p-HO—Ph— 17 p-HO—Ph— —C₄H₈—S—C₄H₈— p-HO—Ph— 18 p-HO—Ph——CH₂CO—S—C₂H₄— p-HO—Ph— 19 p-HO—Ph— —CH₂CO—S—C₃H₆— p-HO—Ph— 20 p-HO—Ph——CH₂CO—S—C₄H₈— p-HO—Ph— 21 p-HO—Ph— —CH₂CO—S—C₄H₆— p-HO—Ph— 22 p-HO—Ph——CH₂CO—S—C₄H₄— p-HO—Ph— 23 p-HO—Ph— —CH(CH₃)CO—S—C₂H₄— p-HO—Ph— 24p-HO—Ph— —C₂H₄CO—S—CH₂CH(OH)CH₂— p-HO—Ph— 25 p-HO—Ph——CH₂CO—S—C₂H₄NHCOCH₂— p-HO—Ph— 26 p-HO—Ph— —C₂H₄CO—S—C₂H₄NHCOC₂H₄—p-HO—Ph— 27 p-HO—Ph— —C₂H₄—O—C₂H₄— p-HO—Ph— 28 p-HO—Ph— —C₂H₄—O—C₃H₆—p-HO—Ph— 29 p-HO—Ph— —C₂H₄—O—C₄H₄— p-HO—Ph— 30 p-HO—Ph— —C₂H₄—O—C₄H₆—p-HO—Ph— 31 p-HO—Ph— —C₂H₄—O—C₄H₈— p-HO—Ph— 32 p-HO—Ph— —C₃H₆—O—C₃H₆—p-HO—Ph— 33 p-HO—Ph— —C₃H₆—O—C₄H₆— p-HO—Ph— 34 p-HO—Ph— —C₃H₆—O—C₄H₈—p-HO—Ph— 35 p-HO—Ph— —C₄H₈—O—C₄H₈— p-HO—Ph— 36 p-HO—Ph— —CH₂CO—O—C₂H₄—p-HO—Ph— 37 p-HO—Ph— —CH₂CO—O—C₃H₆— p-HO—Ph— 38 p-HO—Ph— —CH₂CO—O—C₄H₈—p-HO—Ph— 39 p-HO—Ph— —CH₂CO—O—C₄H₆— p-HO—Ph— 40 p-HO—Ph— —CH₂CO—O—C₄H₄—p-HO—Ph— 41 p-HO—Ph— —CH(CH₃)CO—O—C₂H₄— p-HO—Ph— 42 p-HO—Ph——C₂H₄CO—O—CH₂CH(OH)CH₂— p-HO—Ph— 43 p-HO—Ph— —CH₂CO—O—C₂H₄NHCOCH₂—p-HO—Ph— 44 p-HO—Ph— —C₂H₄CO—O—C₂H₄NHCOC₂H₄— p-HO—Ph—

TABLE 2 Compound No. Ar¹ R² R³ R⁴ Ar² 45 p-HO—Ph— —C₂H₄— —C₂H₄— —Hp-HO—Ph— 46 p-HO—Ph— —C₃H₆— —C₃H₆— —H p-HO—Ph— 47 p-HO—Ph— —C₄H₈— —C₄H₈——H p-HO—Ph— 48 p-HO—Ph— —C₂H₄— —C₂H₄— —OH p-HO—Ph— 49 p-HO—Ph— —C₂H₄——C₂H₄— —C(═NH)NH₂ p-HO—Ph— 50 p-HO—Ph— —C₂H₄— —C₂H₄— —COC₃H₇ p-HO—Ph— 51p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₂CH₂CO₂H p-HO—Ph— 52 p-HO—Ph— —C₂H₄— —C₂H₄——COCH₂CH₂S—Ph—OH-p p-HO—Ph— 53 p-HO—Ph— —C₂H₄— —C₂H₄— —CHO p-HO—Ph— 54p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₃ p-HO—Ph— 55 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂CH₃p-HO—Ph— 56 p-HO—Ph— —C₃H₆— —C₃H₆— —CHO p-HO—Ph— 59 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂CH₂NH₂ p-HO—Ph— 60 p-HO—Ph— —CH₂CO— —C₂H₄— —H p-HO—Ph— 61p-HO—Ph— —CH₂CO— —C₃H₆— —H p-HO—Ph— 62 p-HO—Ph— —CH₂CO— —C₄H₈— —Hp-HO—Ph— 63 p-HO—Ph— —CH₂CO— —C₄H₆— —H p-HO—Ph— 64 p-HO—Ph— —CH₂CO——C₄H₄— —H p-HO—Ph— 65 p-HO—Ph— —CH₂CO— —C₄H₄— —CHO p-HO—Ph— 66 p-HO—Ph——CH(CH₃)CO— —C₂H₄— —H p-HO—Ph— 67 p-HO—Ph— —CH(CH₃)CO— —C₂H₄— —C₂H₄OHp-HO—Ph— 68 p-HO—Ph— —C₂H₄CO— —CH₂CH(OH)CH₂— —C₂H₄OH p-HO—Ph— 69p-HO—Ph— —CH₂CO— —C₂H₄NHCOCH₂— —H p-HO—Ph— 70 p-HO—Ph— —C₂H₄CO——C₂H₄NHCOC₂H₄— —H p-HO—Ph— 71 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₅ p-HO—Ph— 72p-HO—Ph— —C₂H₄— —C₂H₄— —C₃H₇ p-HO—Ph— 73 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂—C≡CH p-HO—Ph— 74 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CH═CH₂ p-HO—Ph— 75p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-cyclopropyl p-HO—Ph— 76 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂—SO₂NH₂ p-HO—Ph— 77 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CN p-HO—Ph—78 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO—NH₂ p-HO—Ph— 79 p-HO—Ph— —C₂H₄——C₂H₄— —C₂H₄—CO—N(CH₃)₂ p-HO—Ph— 80 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—CO—N(C₂H₅)₂ p-HO—Ph— 81 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CO—CH₃p-HO—Ph— 82 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—NH—CO—NH₂ p-HO—Ph— 83 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—NH—CO—CH₃ p-HO—Ph— 84 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂Fp-HO—Ph— 85 p-HO—Ph— —C₂H₄— —C₂H₄— —CF₃ p-HO—Ph— 86 p-HO—Ph— —C₂H₄——C₂H₄— —C₂H₄—(N-succinimido) p-HO—Ph— 87 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—S—CH₃ p-HO—Ph— 88 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-ethyleneacetalp-HO—Ph— 89 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-thienyl) p-HO—Ph— 90 p-HO—Ph——C₂H₄— —C₂H₄— -furfuryl p-HO—Ph— 91 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂-(4-pyridyl) p-HO—Ph— 92 p-HO—Ph— —C₂H₄— —C₂H₄— -o-hydroxybenzylp-HO—Ph— 93 p-HO—Ph— —C₂H₄— —C₂H₄— -m-hydroxybenzyl p-HO—Ph— 94 p-HO—Ph——C₂H₄— —C₂H₄— -p-hydroxybenzyl p-HO—Ph— 95 p-HO—Ph— —C₂H₄— —C₂H₄——(CH₂)₃—OH p-HO—Ph— 96 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—NH—CO—CH₃ p-HO—Ph— 97p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CO—NH₂ p-HO—Ph— 98 p-HO—Ph— —C₂H₄— —C₂H₄—-benzyl p-HO—Ph— 99 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(3-pyridyl) p-HO—Ph— 100p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-pyridyl) p-HO—Ph— 101 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂-(2-quinolinyl) p-HO—Ph— 102 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—OHp-HO—Ph— 103 p-HO—Ph— —C₂H₄— —C₂H₄— —(CH₂)₃—OCH₃ p-HO—Ph— 104 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—OCH₃ p-HO—Ph— 105 p-HO—Ph— —C₂H₄— —C₂H₄—-o-fluorobenzyl p-HO—Ph— 106 p-HO—Ph— —C₂H₄— —C₂H₄— -p-fluorobenzylp-HO—Ph— 107 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO—(N-morpholino) p-HO—Ph— 108p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO-(1-piperidyl) p-HO—Ph— 109 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—N(C₂H₅)₂ p-HO—Ph— 110 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—(N-morpholino) p-HO—Ph— 111 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄-(1-piperidyl) p-HO—Ph— 112 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—CH₃ p-HO—Ph—113 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—C₂H₅ p-HO—Ph— 114 p-HO—Ph— —C₂H₄— —C₂H₄——CO—C₆H₅ p-HO—Ph— 115 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(2-pyridyl) p-HO—Ph—116 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(3-pyridyl) p-HO—Ph— 117 p-HO—Ph— —C₂H₄——C₂H₄— —CO-(4-pyridyl) p-HO—Ph— 118 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—CH₃p-HO—Ph— 119 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—C₆H₅ p-HO—Ph— 120 p-HO—Ph——C₂H₄— —C₂H₄— —CO—NH₂ p-HO—Ph— 121 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—NH(CH₃)p-HO—Ph— 122 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—N(CH₃)₂ p-HO—Ph— 123 p-HO—Ph——C₂H₄— —C₂H₄— —CO—N(C₂H₅)₂ p-HO—Ph— 124 p-HO—Ph— —C₂H₄— —C₂H₄——CO-(N-morpholino) p-HO—Ph— 125 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(1-piperidyl)p-HO—Ph— 126 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—NH—C₆H₅ p-HO—Ph— 127 p-HO—Ph——C₂H₄— —C₂H₄— —CO—NH-(2-pyridyl) p-HO—Ph— 128 p-HO—Ph— —C₂H₄— —C₂H₄——SO₂—NH₂ p-HO—Ph— 129 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—N(C₂H₅)₂ p-HO—Ph— 130p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂-(N-morpholino) p-HO—Ph— Compound No. 57

Compound No. 58

TABLE 3 131 B—B 132 B—CH₂—B 133 B—C₂H₄—B 134 B—C₃H₆—B 135 B—C₄H₈—B 136B—C₅H₁₀—B 137 B—C₆H₁₂—B 138 B—C₇H₁₄—B 139 B—C₈H₁₆—B 140 B—C₉H₁₈—B 141B—C₁₀H₂₀—B 142 B—C₁₁H₂₂—B 143 B-C₂H₄—SO₂—C₂H₄—SO₂—C₂H₄—B 144 B—CH(CH₃)—B145 B—CH(C₂H₅)—B 146 B—CH(n-C₃H₇)—B 147 B—CH(C₆H₅)—B 148B—CH(B)(p-HOC₂H₄O—C₆H₄—) 149 B—C(CH₃)₂—B 150 B—CH(COOH)—B 151B—CH(C₂H₄OH)—B 152 B—CH(CH₃)—CH₂—B 153 B—CH(C₂H₄OH)—CH₂—B 154B—CH(COOH)—CH₂—B 155 B—CH(C₂H₅)—CH₂—B 156 B—CH₂—CH(OH)—CH₂—B 157B—CH₂—C(CH₂B)₂—CH₂—B 158 B—CH₂—S—CH₂—B 159 B—CH₂—CH═CH—CH₂—B 160B—CH₂—C≡C—CH₂—B 161 B—CH₂—C₆H₄—CH₂—B(—C₆H₄— is a o-phenylene group) 162B—C₂H₄—O—CH₂—O—C₂H₄—B 163 B—C₂H₄—O—C₂H₄—O—C₂H₄—B 164B—CH₂—COO—C₂H₄—OCOCH₂—B 165 B—CH₂—COO—C₃H₆—OCOCH₂—B 166B—CH₂CH(OH)CH₂—O—C₂H₄—O—CH₂CH(OH)CH₂—B 167B—(C₂H₄O)₂—CO—CH₂—CO—(C₂H₄O)₂—B 168B—(C₂H₄O)₂—CO-(trans)CH═CH—CO—(C₂H₄O)₂—B 169 B—CH₂—COO—(C₂H₄O)₃—CO—CH₂—B170 B—CH₂—COO—(C₂H₄O)4-CO—CH₂—B 171 B—(C₂H₄O)₃—C₂H₄—B 172B—(C₂H₄O)₄—C₂H₄—B 173 B—(C₂H₄O)₅—C₂H₄—B 174 B—(C₂H₄O)₃—CO—(C₂H₄O)₃—B 175B—(C₂H₄O)₂—CO—C₂H₄—CO—(C₂H₄O)₂—B Compound No. 176

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Compound No. 185

[B—CH₂—CO—]₂ Compound No. 186 B—CO—CH₂—CO—B Compound No. 187

Compound No. 188 Compound No. 189 Compound No. 190

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According to the present invention, there are provided novel compoundsrepresented by the general formula (XII):

Ar²³—S—R²²—N(R²⁴)—R²³—S—Ar²⁴.

Ar²³ and Ar²⁴ in the general formula (XII) have the same meanings as theaforementioned Ar¹ and Ar². However, those wherein each of Ar²³ and Ar²⁴is a phenyl group having one hydroxyl group on the ring, and both ofthese phenyl groups have a tertiary alkyl group at a position on thering adjacent to the hydroxyl group are excluded from the scope of theinvention concerning the novel compounds of the present invention. R²²,R²³ and R²⁴ in the general formula (XII) have the same meanings as theaforementioned R², R³, and R⁴, provided that, when R²² and R²³ do notform a ring. R²²—N(R²⁴)—R²³ except for the part of R²⁴ does not containan amide bond. Furthermore, in the above definitions, R¹²⁵, R¹²⁶, R¹²⁷,R^(101A), R^(101B), R^(101C), and R^(101D) have the same meanings asR²⁵, R²⁶, R²⁷, R^(1A), R^(1B), R^(1C) and R^(1D), respectively.

Examples of the divalent group suitable as R²², R²³, or R²²—N(R²⁴)—R²³will be exemplified below. However, the divalent group which can be usedfor the compound of the present invention is not limited to theseexamples.

Particularly preferred compounds of the present invention represented bythe formula (XII) will be specifically exemplified below. However, thecompounds of the present invention are not limited to the followingexemplary compounds.

TABLE 4 Compound No. Ar²³ R²² R²³ R²⁴ Ar²⁴ 45 p-HO—Ph— —C₂H₄— —C₂H₄— —Hp-HO—Ph— 46 p-HO—Ph— —C₃H₆— —C₃H₆— —H p-HO—Ph— 47 p-HO—Ph— —C₄H₈— —C₄H₈——H p-HO—Ph— 48 p-HO—Ph— —C₂H₄— —C₂H₄— —OH p-HO—Ph— 49 p-HO—Ph— —C₂H₄——C₂H₄— —C(═NH)NH₂ p-HO—Ph— 50 p-HO—Ph— —C₂H₄— —C₂H₄— —COC₃H₇ p-HO—Ph— 51p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₂CH₂CO₂H p-HO—Ph— 52 p-HO—Ph— —C₂H₄— —C₂H₄——COCH₂CH₂S—Ph—OH-p p-HO—Ph— 53 p-HO—Ph— —C₂H₄— —C₂H₄— —CHO p-HO—Ph— 54p-HO—Ph— —C₂H₄— —C₂H₄— —COCH₃ p-HO—Ph— 55 p-HO—Ph— —C₃H₆— —C₃H₆— —CHOp-HO—Ph— 56 p-HO—Ph— —C₃H₆— —C₃H₆— —COCH₂Cl p-HO—Ph— 59 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂CH₂NH₂ p-HO—Ph— 71 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₅ p-HO—Ph— 72p-HO—Ph— —C₂H₄— —C₂H₄— —C₃H₇ p-HO—Ph— 73 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂—C≡CH p-HO—Ph— 74 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CH═CH₂ p-HO—Ph— 75p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-cyclopropyl p-HO—Ph— 76 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂—SO₂NH₂ p-HO—Ph— 77 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CN p-HO—Ph—78 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO—NH₂ p-HO—Ph— 79 p-HO—Ph— —C₂H₄——C₂H₄— —C₂H₄—CO—N(CH₃)₂ p-HO—Ph— 80 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—CO—N(C₂H₅)₂ p-HO—Ph— 81 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CO—CH₃p-HO—Ph— 82 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—NH—CO—NH₂ p-HO—Ph— 83 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—NH—CO—CH₃ p-HO—Ph— 84 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂Fp-HO—Ph— 85 p-HO—Ph— —C₂H₄— —C₂H₄— —CF₃ p-HO—Ph— 86 p-HO—Ph— —C₂H₄——C₂H₄— —C₂H₄-(N-succinimido) p-HO—Ph— 87 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—S—CH₃ p-HO—Ph— 88 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-ethyleneacetalp-HO—Ph— 89 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-thienyl) p-HO—Ph— 90 p-HO—Ph——C₂H₄— —C₂H₄— -furfuryl p-HO—Ph— 91 p-HO—Ph— —C₂H₄— —C₂H₄——CH₂-(4-pyridyl) p-HO—Ph— 92 p-HO—Ph— —C₂H₄— —C₂H₄— -o-hydroxybenzylp-HO—Ph— 93 p-HO—Ph— —C₂H₄— —C₂H₄— -m-hydroxybenzyl p-HO—Ph— 94 p-HO—Ph——C₂H₄— —C₂H₄— -p-hydroxybenzyl p-HO—Ph— 95 p-HO—Ph— —C₂H₄— —C₂H₄——(CH₂)₃—OH p-HO—Ph— 96 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—NH—CO—CH₃ p-HO—Ph— 97p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂—CO—NH₂ p-HO—Ph— 98 p-HO—Ph— —C₂H₄— —C₂H₄—-benzyl p-HO—Ph— 99 p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(3-pyridyl) p-HO—Ph— 100p-HO—Ph— —C₂H₄— —C₂H₄— —CH₂-(2-pyridyl) p-HO—Ph— 101 p-HO—Ph— —C₂H₄——C₂H₄— —CH₂-(2-quinolinyl) p-HO—Ph— 102 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—OHp-HO—Ph— 103 p-HO—Ph— —C₂H₄— —C₂H₄— —(CH₂)₃—OCH₃ p-HO—Ph— 104 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—OCH₃ p-HO—Ph— 105 p-HO—Ph— —C₂H₄— —C₂H₄—-o-fluorobenzyl p-HO—Ph— 106 p-HO—Ph— —C₂H₄— —C₂H₄— -p-fluorobenzylp-HO—Ph— 107 p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO—(N-morpholino) p-HO—Ph— 108p-HO—Ph— —C₂H₄— —C₂H₄— —C₂H₄—CO-(1-piperidyl) p-HO—Ph— 109 p-HO—Ph——C₂H₄— —C₂H₄— —C₂H₄—N(C₂H₅)₂ p-HO—Ph— 110 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄—(N-morpholino) p-HO—Ph— 111 p-HO—Ph— —C₂H₄— —C₂H₄——C₂H₄-(1-piperidyl) p-HO—Ph— 112 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—CH₃ p-HO—Ph—113 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—C₂H₅ p-HO—Ph— 114 p-HO—Ph— —C₂H₄— —C₂H₄——-CO—C₆H₅ p-HO—Ph— 115 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(2-pyridyl) p-HO—Ph—116 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(3-pyridyl) p-HO—Ph— 117 p-HO—Ph— —C₂H₄——C₂H₄— —CO-(4-pyridyl) p-HO—Ph— 118 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—CH₃p-HO—Ph— 119 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—C₆H₅ p-HO—Ph— 120 p-HO—Ph——C₂H₄— —C₂H₄— —CO—NH₂ p-HO—Ph— 121 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—NH(CH₃)p-HO—Ph— 122 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—N(CH₃)₂ p-HO—Ph— 123 p-HO—Ph——C₂H₄— —C₂H₄— —CO—N(C₂H₅)₂ p-HO—Ph— 124 p-HO—Ph— —C₂H₄— —C₂H₄——CO-(N-morpholino) p-HO—Ph— 125 p-HO—Ph— —C₂H₄— —C₂H₄— —CO-(1-piperidyl)p-HO—Ph— 126 p-HO—Ph— —C₂H₄— —C₂H₄— —CO—NH—C₆H₅ p-HO—Ph— 127 p-HO—Ph——C₂H₄— —C₂H₄— —CO—NH-(2-pyridyl) p-HO—Ph— 128 p-HO—Ph— —C₂H₄— —C₂H₄——SO₂—NH₂ p-HO—Ph— 129 p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂—N(C₂H₅)₂ p-HO—Ph— 130p-HO—Ph— —C₂H₄— —C₂H₄— —SO₂-(N-morpholino) p-HO—Ph— Compound No. 57

Compound No. 58

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Compound No. 227

Compound No. 228

The compounds of the present invention may form an acid addition salt,and may also form a base addition salt depending on the types ofsubstituents. Examples of the acid addition salt include, but notlimited thereto, mineral acid salts such as hydrochlorides, sulfates andnitrates, and organic acid salts such as p-toluenesulfonates,methanesulfonates, acetates, chloroacetates, oxalates,trifluoromethanesulfonates, and quinolinesulfonates. When they form abase addition salt, metal salts such as sodium salts and potassiumsalts, ammonium salts such as ammonium salts and triethylammonium saltsand the like may be used. The compounds of the present invention mayalso form intramolecular zwitter ions based on a phenolic hydroxyl groupand a basic group, which also fall within the scope of the presentinvention. Furthermore, the compounds of the aforementioned formula (XI)and formula (XII) in free form or any salts thereof, and any hydrates orany solvates of the compounds in free form or salts thereof fall withinthe scope of the present invention. Solvents that can form solvates arenot particularly limited. For example, the solvate may be formed withmethanol, ethanol, acetone, tetrahydrofuran, dichloromethane,chloroform, dimethylformamide or the like.

The compounds of the present invention may have one or more asymmetriccarbons depending on the types of the substituents. Furthermore, asulfur atom may also serve as an asymmetric center. Any optical isomersin optically pure form based on one or more asymmetric carbons, mixturesof the optical isomers, racemates, diastereomers based on two or moreasymmetric carbons, mixtures of the diastereomers and the like all fallwithin the scope of the present invention.

Two or three groups selected from R²², R²³, and R²⁴ may bind to eachother, via a divalent group if required, to form a saturated orunsaturated cyclic structure. In that case, the nitrogen atom to whichR²⁴ binds may be an atom that constitutes the ring. Examples of the ringinclude, for example, pyrrole ring, piperidine ring, indole ring,pyridine ring, triazine ring, pyrimidine ring, quinoline ring, oxazinering, indazole ring, thiazole ring and the like. These rings may have apartially or completely reduced ring structure. Furthermore, thosewherein one more monovalent group such as an alkyl group further bindsto the nitrogen atom to which R²⁴ binds to form a quaternary salt alsofall within the scope of the present invention. The counter ion of thequaternary salt may be, for example, iodide ion, bromide ion, chlorideion, perchlorate ion and the like. As the monovalent group, C₁₋₆ alkylgroups such as methyl group and the like are preferred.

The methods for preparing the bisaryl compounds represented by theaforementioned general formulas (I), (II) and (XII) are not particularlylimited, and they can be synthesized via various synthetic routes.Methods for preparing typical compounds of the present invention arespecifically disclosed in Examples set out below, and accordingly, thoseskilled in the art will readily prepare bisaryl compounds falling withinthe scopes of the aforementioned general formulas by referring to themethod described in Examples, adding suitable alterations andmodifications to the methods, if required, and suitably choosingstarting materials and reagents. For the preparation, one step, orseveral combined steps selected from various condensation, addition,oxidation, and reduction reactions and the like can be used. Thesereactions are detailed in literature. For example, various methodsmentioned as unit operations and starting materials disclosed in “JikkenKagaku Koza” (Maruzen Co., Ltd., each separate volume of the first tothe 4th edition are available) can be preferably used.

For example, it may be preferable to use a mercapto compound, an aminecompound and the like for a starting material from viewpoints of areaction operation and an yield. For example, unit operations such assynthesis of thioether (sulfide) and synthesis of ester; reactions ofmercapto group with reactive functional groups such as vinyl group,halogen atoms (including haloalkyl groups), epoxy group, aziridine ring,acyl halide groups, and isocyanate group; and amination reaction,amidation reaction, alkylation reaction and the like are well known tothose skilled in the art. Therefore, it is possible to chose suitablemethods from the conventional methods considering an yield, easiness ofreaction and the like.

For example, in these production methods, when any of the defined groupsare changed under the condition of the reaction steps, or unsuitable toproceed the reaction steps, desired steps may be efficiently performedby using techniques commonly used in the synthetic organic chemistry,for example, protection and deprotection of functional groups, ortreatments including oxidation, reduction, and hydrolysis. Isolation andpurification of synthetic intermediates and target compounds in theaforementioned steps can be performed by common techniques in the fieldof synthetic organic chemistry, for example, filtration, extraction,washing, drying, concentration, recrystallization, variouschromatography methods and the like. In addition, syntheticintermediates may be used in subsequent steps without isolation.

EXAMPLES

The present invention will be more specifically explained with referenceto the following examples. However, the scope of the present inventionis not limited to these examples. The compound numbers used in theexamples correspond to the compound numbers shown in the aforementionedtables.

Example 1 Synthesis of Compound 45

Bis(2-chloroethyl)amine hydrochloride (17.8 g) and thiohydroquinone(25.2 g) were added to a 1,000 ml flask provided with a stirrer and acondenser, and methanol (300 ml) was added thereto for dissolution. Tothis solution, a 28% solution (57.9 g) of sodium methoxide in methanolwas added dropwise at room temperature. After the addition wascompleted, the reaction mixture was stirred under reflux by heating for3 hours, and then left standing for one day. The reaction mixture wastransferred to a 3 liter-beaker, 1,500 ml of water was added, and thedeposited product was separated. The crude product was recrystallizedfrom methanol to obtain 20 g of the target compound (m.p. 133-134° C.).

¹H-NMR (DMSO-d₆) δ (ppm) 2.61 (t, 4H), 2.83 (t, 4H), 3.38 (s, 1H), 6.72(dd, 4H), 7.20 (dd, 4H), 9.55 (s, 2H)

Example 2 Synthesis of Compound 113

In a 100 ml three-neck flask, Compound 45 (3.2 g) synthesized in Example1 was dissolved in dimethylacetamide (15 ml), and propionic anhydride(1.4 ml) was dropwise added thereto under ice cooling. The reactionmixture was stirred for 1 hour at room temperature, poured into dilutedhydrochloric acid, and extracted with ethyl acetate. The organic layerwas washed with saturated brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (ethyl acetate/hexane=7/3-1/1) toobtain 3.58 g of the target compound.

¹H-NMR (DMSO-d₆) δ (ppm) 0.37 (t, 3H), 2.04 (q, 2H), 2.90 (m, 4H), 3.30(m, 4H), 6.76 (d, 4H), 7.20 (d, 4H), 9.57 (s, 1H), 9.60 (s, 1H)

Example 3 Synthesis of Compound 61

3-Bromopropylamine hydrobromide (50.0 g) and methylene chloride (300 ml)were put into a 1,000 ml flask provided with a stirrer and a condenser,and triethylamine (46 g) was added thereto at a temperature below 10° C.Then, bromoacetyl chloride (36 g) was added dropwise to the mixturewhile keeping the temperature of the reaction mixture at 20° C. or below20° C., and then the mixture was stirred for 1 hour. The organic layerwas separated by filtration and concentrated, and the residue waspurified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=2:1) to obtain (3-bromopropyl)-1-bromoacetamide(yield: 24%). Thiohydroquinone (5.0 g) and(3-bromopropyl)-1-bromoacetamide (5.8 g) were added to methanol (50 ml),and 28% sodium methoxide (7.6 g) was added thereto with stirring and themixture was stirred at 40° C. for 2 hours. Water (200 ml) was added tothe reaction mixture, the mixture was extracted with ethyl acetate, andthe organic phase was dried. The product obtained after evaporation ofthe solvent was treated with acetonitrile to obtain crystals (m.p.122-124° C.).

Example 4 Synthesis of Compound 1

2,6-Dichloromethylpyridine (3.5 g), and thiohydroquinone (5.0 g) wereput into a 100 ml flask provided with a stirrer and a condenser, andmethanol (20 ml) and a 28% solution (7.7 g) of sodium methoxide inmethanol were added thereto at room temperature. The mixture was warmedto 60° C., and stirred for 1 hour at the same temperature. After themethanol was evaporated, the organic phase was extracted with ethylacetate. The organic phase was dried and concentrated to obtain crystalsof the target compound. The product was recrystallized from acetonitrileto obtain the target compound (yield: 70%, m.p. 140-140.5° C.).

Example 5 Synthesis of Compound 27

Methanol (40 ml) was put into a flask provided with a stirrer,thiohydroquinone (0.08 mol) and 48% aqueous NaOH (0.084 mol) were addedthereto, and then bis-2-chloroethyl ether (0.04 mol) was dropwise addedthereto with stirring at room temperature. The mixture was maintained at40° C. for 4 hours, then added to water (300 ml) and extracted withethyl acetate. The organic phase was washed with water and dried, andthe solvent was evaporated to obtain crude crystals of the targetcompound. The crystals were recrystallized from benzene to obtain thetarget compound (yield: 82%, m.p. 91-92° C.).

Example 6 Synthesis of Compound 162

β,β′-Dichlorodiethylformal was synthesized according to the method ofVinokurov D. M. The target compound was obtained in the same manner asin Example 5 except that the above-obtained compound was used as ahalide starting material. The target compound was obtained throughrecrystallization from a mixed solvent of water and methanol (yield:81%, m.p. 108-110° C.)

Example 7 Synthesis of Compound 124

Compound 45 (10.0 g) obtained in Example 1 was put into a 500 ml flaskprovided with a stirrer and a calcium chloride tube, anddimethylacetamide (100 ml) was added thereto for dissolution. To thissolution was added triethylamine (7.78 ml) and 4-morpholinecarbonylchloride (4.17 g), the mixture was stirred for 2 hours, then water wasadded thereto and the mixture was further made neutral with hydrochloricacid. The organic layer was extracted with ethyl acetate, washed withwater (3 times) and with saturated brine (2 times), then dried andconcentrated to obtain 8.30 g of Compound 124 (semi-solid).

¹H-NMR (DMSO-d₆) δ (ppm) 2.86 (t, 4H), 2.87 (t, 4H), 3.20 (t, 4H), 3.33(t, 4H), 6.74(d, 4H), 7.23 (d, 4H), 9.61(s, 2H)

Example 8 Synthesis of Compound 97

Compound 45 (964 mg) obtained in Example 1 was put into a 20 ml flaskprovided with a calcium chloride tube, and dimethylformamide (5 ml) wasadded thereto for dissolution. To this solution was added sodiumhydrogen carbonate (1 g), potassium iodide (166 mg) and chloroacetamide(300 mg), and the mixture was stirred at 80° C. for 2 hours. Thereaction mixture was added to water, the mixture was extracted withethyl acetate, and the organic layer was washed with water (3 times) andsaturated brine (2 times), then dried and concentrated. The residue waspurified by silica gel chromatography (eluent: methylene chloride/ethylacetate=213), and the solvent was concentrated. The residue wascrystallized by adding hexane, filtered, washed and dried to obtain 900mg of Compound 97 (m.p. 105-106° C.).

¹H-NMR (CD₃OD) δ (ppm) 2.72 (t, 4H), 2.82 (t, 4H), 3.10 (s, 2H), 6.80(d, 4H), 7.30 (d, 4H)

Example 9 Synthesis of Compound 190

2-Fluorophenol (4.05 g), water (50 ml), copper sulfate pentahydrate(18.0 g), and ammonium thiocyanate (11.0 g) were successively put into a300 ml flask provided with a stirrer, and the mixture was stirred for 4hours on a water bath (50° C.). The solid was removed by filtration, andthe filtrate was extracted with ethyl acetate, then dried andconcentrated. The residue was purified by silica gel chromatography(eluent: hexane/ethyl acetate=10/1.5) to obtain 1.61 g of3-fluoro-4-hydroxybenzothiocyanate.

¹H-NMR (CDCl₃)δ (ppm) 5.79 (s, 1H), 7.07 (dd, 1H), 7.28 (dd, 1H), 7.36(dd, 1H)

The resulting 3-fluoro-4-hydroxybenzothiocyanate (0.45 g) was put into anitrogen-purged 50 ml flask provided with a stirrer, and dissolved intetrahydrofuran (5.0 ml). The solution was cooled to 0° C., aluminiumlithium hydride (0.10 g) was added thereto, and then the mixture wasstirred at room temperature for 20 minutes. To the mixture was thenadded ethyl acetate and saturated aqueous ammonium chloride, and themixture was neutralized with diluted hydrochloric acid. The organiclayer was extracted with ethyl acetate, dried and concentrated. Theresidue was purified by silica gel chromatography (eluent: hexane/ethylacetate=10/1.5) to obtain 0.13 g of 3-fluoro-4-hydroxythiophenol.

¹H-NMR (CDCl₃)δ (ppm) 3.42 (s, 1H), 5.52 (s, 1H), 6.88 (dd, 1H), 7.00(dd, 1H), 7.08 (dd, 1H)

The 3-fluoro-4-hydroxythiophenol (0.13 g) obtained above was put into a50 ml flask provided with a stirrer, and dissolved in methanol (5.0 ml).The solution was bubbled with nitrogen gas for about 15 minutes fordeairing, sodium methoxide (28%, 0.20 ml) and bis(2-chloroethyl) ether(0.52 ml) were added thereto, and then the mixture was stirred for 2hours (40° C.). The mixture was neutralized with diluted hydrochloricacid, and the organic layer was extracted with ethyl acetate, dried andconcentrated. The residue was purified by silica gel chromatography(eluent: hexane/ethyl acetate=5/1) to obtain 56 mg of Compound 190 (m.p.87-88° C.).

1H-NMR (CDCl₃) δ (ppm) 2.95 (t, 4H), 3.55 (t, 4H), 6.89 (dd, 1H), 7.03(dd, 1H), 7.12 (dd, 1H)

Example 10 Synthesis of Compound 191

5-Norbornene-2-dicarboxylic acid anhydride (1.30 g),2-(4-hydroxyphenylthio)propylamine (3.66 g), and triethylamine (2.02 g)were put into a 200 ml flask provided with a stirrer and a condenser,dimethylformamide (50 ml) was added thereto for dissolution, and thenthe solution was stirred at room temperature for 17 hours. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with 1 N hydrochloric acidand then with saturated aqueous sodium hydrogen carbonate, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluent:dichloromethane/ethyl acetate=2/8) to obtain 1.76 g of Compound 191 as asemi-solid substance.

¹H-NMR (DMSO-d₆) δ (ppm) 1.20 (s, 2H), 1.51 (t, 4H), 2.72 (t, 4H), 2.90(s, 2H), 2.98 (q, 4H), 3.03 (s, 2H), 6.07 (s, 2H), 6.72 (d, 4H), 7.34(d, 2H), 9.56 (s, 2H)

Example 11 Synthesis of Compound 192

1-Cyclopentane diacetic acid (0.93 g) was put into a 100 ml flaskprovided with a stirrer and a condenser and tetrahydrofuran (35 ml) wasadded thereto for dissolution. Then, to the solution was addeddicyclohexylcarbodiimide (2.06 g) and 2-(4-hydroxyphenylthio)propylamine(1.83 g), and the mixture was stirred at 40° C. for 6 hours. Insolublematerials were removed from the reaction mixture by suction filtration,and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel chromatography (eluent: hexane/ethylacetate=1/1) to obtain 1.09 g of Compound 192 as a semi-solid substance.

¹H-NMR (DMSO-d₆) δ (ppm) 1.18 (t, 2H), 1.58 (m, 4H), 2.13 (s, 2H), 2.76(t, 2H), 3.14 (dd, 2H), 6.72 (d, 2H), 7.20 (d, 2H), 8.08 (t, 1H), 9.55(s, 1H)

Example 12 Synthesis of Compound 100

Compound 45 (1.79 g) obtained in Example 1 was put into a 50 ml flaskprovided with a calcium chloride tube and dimethylformamide (15 ml) wasadded thereto for dissolution. To this solution was added sodiumhydrogen carbonate (1.68 g) and 2-chloromethylpyridine hydrochloride(820 mg), and the mixture was stirred at 70° C. for 4 hours. Thereaction mixture was added to water and the mixture was extracted withethyl acetate. The extract was washed with water (3 times) and saturatedbrine (2 times), dried, and then concentrated. The residue was purifiedby silica gel chromatography (eluent: methylene chloride/methanol=20/1),the solvent was concentrated, and the residue was crystallized by addinghexane, and then filtered to obtain 1.57 g of Compound 100 (m.p. 80-81°C.).

1H-NMR (DMSO-d₆) δ (ppm) 2.60 (t, 4H), 2.85 (t, 4H), 3.68 (s, 2H), 6.68(d, 4H), 7.15 (d, 4H), 7.25 (t, 1H), 7.41 (d, 1H), 7.70 (t, 1H), 8.42(d, 1H), 9.55 (s, 2H)

Example 13 Synthesis of Compound 193

Compound 97 (1.00 g) obtained in Example 8 was put into a 100 ml flaskprovided with a calcium chloride tube at room temperature, andacetonitrile (10 ml) was added thereto for dissolution. To this solutionwas added pyridine (2.1 ml) and acetic anhydride (0.75 ml), and themixture was stirred at room temperature for 4.5 hours. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (100 ml), and then washed with 1 Nhydrochloric acid (50 ml×2). The organic layer was separated, and driedover anhydrous sodium sulfate, and then the solvent was evaporated toobtain 1.17 g of the target compound (yield: 89%, m.p. 139-142° C.).

¹H-NMR (CD₃OD) δ (ppm) 2.30 (s, 6H), 3.15-3.50 (m, 8H), 4.12 (s, 2H),7.12 (d, 4H), 7.50 (d, 4H)

Example 14 Synthesis of Compound 71

The reaction of Example 12 was repeated by using 940 mg of ethyl iodideinstead of 2-chloromethylpyridine hydrochloride, and the product waspurified by silica gel chromatography (eluent: methylenechloride/methanol=20/1) to obtain Compound 71 (1.49 g) as oil.

¹H-NMR (DMSO-d₆) δ (ppm) 0.89 (t, 3H), 2.48 (q, 2H), 2.60 (t, 4H), 2.80(t, 4H), 6.78 (d, 4H), 7.25 (d, 4H), 9.62 (s, 2H)

Example 15 Syntheses of Compounds 72 to 81, Compounds 84 to 88, Compound95, Compounds 102 to 103, Compounds 107 to 111, Compound 194, Compounds197 to 201, Compounds 203 to 211 and Compound 213

The title compounds were synthesized in the same manner as in Example 14by allowing Compound 45 obtained in Example 1 to react withcorresponding alkylating agents.

Example 16 Syntheses of Compounds 89 to 91, Compounds 98 to 99, Compound101, Compounds 105 to 106 and Compound 196

The title compounds were synthesized in the same manner as in Example 12by allowing Compound 45 obtained in Example 1 to react withcorresponding arylmethyl halides or heteroarylmethyl halides.

Example 17 Synthesis of Compound 92

Compound 92 was synthesized in accordance with the following syntheticscheme.

Salicyl aldehyde (12.2 g), imidazole (7.2 g), and dimethylformamide (70ml) were put into a 200 ml three-neck flask for dissolution,tert-butyldimethylsilyl chloride (16 g) was added thereto at roomtemperature and the mixture was stirred at room temperature for 1 hour.Then, the reaction mixture was poured into water, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate, and concentrated underreduced pressure to obtain Compound 92A (23.5 g) as oil. The resultingCompound 92A was used for the subsequent reaction without furtherpurification.

Compound 92A (18.9 g) was dissolved in 120 ml of methanol, and sodiumborohydride (760 mg) was added thereto. The reaction mixture was stirredat room temperature for 1 hour, and then poured into water and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over magnesium sulfate, and concentratedunder reduced pressure to obtain Compound 92B (18.8 g) as oil. Theresulting Compound 92B was used for the subsequent reaction withoutfurther purification.

Compound 92B (9.5 g), triethylamine (5.6 ml), andN,N-dimethylaminopyridine (500 mg) were dissolved in acetonitrile (50ml), and methanesulfonyl chloride (4.6 g) was dropwise added thereto.The reaction mixture was left standing at room temperature overnight.The produced triethylamine hydrochloride was filtered, and the filtratewas concentrated under reduced pressure. To the residue was addedhexane, and insoluble materials were removed by filtration. Then, thefiltrate was washed with aqueous citric acid, water, and then saturatedbrine, then, dried over magnesium sulfate and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent: hexane) to obtain Compound C (7.0 g) as oil.

Compound 45 (4.8 g) synthesized in Example 1 and dimethylacetamide (40ml) were put into a 100 ml three-neck flask for dissolution, andCompound 92B (4.1 g) was added thereto. The reaction mixture was stirredat 80° C. for 1 hour, and then poured into water and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate, and concentrated underreduced pressure. The residue was dissolved in methylene chloride (70ml), 10 ml of 1 M solution of tetrabutylammonium fluoride intetrahydrofuran was added thereto, and then the mixture was allowed toreact at room temperature for 1 hour. The reaction mixture was pouredinto water, and the mixture was extracted with methylene chloride. Theorganic layer was washed with saturated brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (eluent: methylenechloride/methanol=100/3) to obtain Compound 92 (4.93 g) as an amorphous.

Example 18 Syntheses of Compound 93 and Compound 94

The title compounds were synthesized in the same manner as in Example 17by allowing Compound 45 obtained in Example 1 to react with benzylchloride substituted with corresponding protected hydroxyl group, andthen deprotecting the product.

Example 19 Syntheses of Compound 50, Compound 51 and Compound 54

The title compounds were synthesized in the same manner as in Example 2by allowing Compound 45 obtained in Example 1 to react with acorresponding acid anhydride.

Example 20 Synthesis of Compound 53

Compound 45 (2.0 g) obtained in Example 1, formic acid (290 mg), anddicyclohexylamide (1.4 g) were stirred in a mixed solvent of chloroform(20 ml) and dimethyl sulfoxide (20 ml) at room temperature for 4 hours.The reaction mixture was filtered, and the residue was washed with ethylacetate. Then, the filtrate and the washing filtrate were combined, andwashed with water, saturated aqueous sodium hydrogen carbonate, and thensaturated brine. The organic layer was dried over sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain 2.1 g of the targetcompound.

¹H-NMR (DMSO-d₆) δ (ppm) 2.87 (m, 2H), 2.95 (m, 2H), 3.30 (m, 2H), 3.37(m, 2H), 6.75 (d, 4H), 7.22 (d, 4H), 7.90 (s, 1H), 9.58 (broad, 2H)

Example 21 Synthesis of Compound 114

Compound 45 (9.64 mg) synthesized in Example 1, pyridine (0.25 ml), anddimethylacetamide (5 ml) were added to a 30 ml three-neck flask fordissolution. To the solution was added dropwise benzoyl chloride (5.34mg) under ice cooling, and the mixture was stirred for 30 minutes underice cooling, and then for 1 hour at room temperature. The reactionmixture was poured into diluted hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate, and then concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: methylene chloride/methanol=10014), andcrystallized by adding hexane to obtain 510 mg of the target compound.

Example 22 Syntheses of Compound 115, Compound 116 and Compound 117

The title compounds were synthesized in the same manner as in Example 22by allowing Compound 45 obtained in Example 1 to react with acorresponding acid chloride, and purifying the product with a silica gelcolumn.

Example 23 Synthesis of Compound 125

The title compound was synthesized in the same manner as in Example 7 byallowing Compound 45 obtained in Example 1 to react withpiperidinocarbonyl chloride.

Example 24 Synthesis of Compound 214

Compound 45 (1.29 g) obtained in Example 1 and D-mannose (1.01 g) werestirred in ethanol (5 ml) at 100° C. for 4 hours on an oil bath. To thereaction mixture was added ethyl acetate (50 ml), the mixture wassubjected to suction filtration, and then the filtrate was concentrated.The resulting residue was purified by silica gel column chromatography(methylene chloride/methanol=911) to obtain 1.05 g of the targetcompound.

¹H-NMR (DMSO-d₆) δ (ppm) 2.73 (m, 4H), 2.83 (m, 4H), 3.55-3.80 (m, 3H),4.30-4.50 (m, 3H), 5.13 (s, 1H), 6.76 (d, 4H), 7.22 (d, 4H), 9.55 (s,2H)

Example 25 Syntheses of Compounds 215 to 219

The title compounds were synthesized in the same manner as in Example 24by allowing Compound 45 obtained in Example 1 to react with acorresponding saccharide.

Example 26 Synthesis of Compound 59

Compound 45 (500 mg) obtained in Example 1,N-{2-(p-toluenesulfonyloxy)ethyl}phthalimide (537 mg), potassium iodide(258 mg), and sodium hydrogen carbonate (131 mg) were stirred indimethylformamide (8 ml) at 150° C. for 28 hours. The reaction mixturewas extracted with ethyl acetate, and the organic layer was washed withsaturated aqueous sodium hydrogen carbonate, dried over magnesiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography to obtain 260 mg ofphthalimide compound.

The above phthalimide compound (260 mg) and hydrazine monohydrate (31.58mg) were stirred in ethanol (3 ml) with heating for 3 hours. Thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with saturated aqueous sodium hydrogen carbonate, dried overmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(chloroform/methanol=1/1) to obtain 97 mg of the target compound.

¹H-NMR (DMSO-d₆) δ (ppm) 2.10 (m, 2H), 2.50-3.00 (m, 10H), 6.87 (d, 4H),7.27 (d, 4H)

Example 27 Syntheses of Compounds 82 to 83, Compound 195 and Compound202

The title compounds were synthesized by allowing Compound 59 obtained inExample 26 to react with sodium isocyanate, acetic anhydride,methanesulfonyl chloride and 3,5-dimethylpyrazole-1-carboxyamidinenitrate, respectively.

Example 28 Synthesis of Compound 48

4-(2-Bromoethylthio)phenol (1.2 g) was dissolved in dimethylformamide(10 ml) under nitrogen atmosphere, to this solution was added imidazole(1.5 g) and tert-butyldimethylsilyl chloride (2.45 g), and the mixturewas stirred at room temperature for one and a half hours. To thereaction mixture was added water, the mixture was extracted withchloroform, and then the organic layer was dried over sodium sulfate,and concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain 1.4 g of silylcompound.

The above silyl compound (1.4 g) and hydroxylamine hydrochloride (150mg) were mixed in ethanol (10 ml), sodium carbonate (400 mg) was addedthereto, and the mixture was refluxed by heating for 8 hours. Thereaction mixture was filtered, and the residue obtained by concentratingthe filtrate under reduced pressure was purified by silica gel columnchromatography (ethyl acetate/hexane=1/4) to obtain 506 mg ofhydroxylamine compound.

The above hydroxylamine compound (480 mg) was dissolved in chloroform(10 ml), to the solution was added a solution of tetrabutylammoniumfluoride in tetrahydrofuran (1 equivalent) and the mixture was stirredat room temperature for 20 minutes. The reaction mixture wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography, and recrystallized from achloroform-hexane mixed solvent to obtain 320 mg of the target compound.

¹H-NMR (DMSO-d₆) δ (ppm) 2.85 (m, 6H), 3.00 (m, 2H), 6.77 (d, 4H), 7.22(d, 4H), 8.98 (broad, 2H)

Example 29 Synthesis of Compound 49

Compounds 45 (200 mg) synthesized in Example 1 and3,5-dimethylpyrazole-1-carboxyamidine nitrate (125 mg) were dissolved indimethyl sulfoxide (4 ml). To this solution was added triethylamine (1.5ml) and the mixture was stirred at 120° C. by heating for 4 hours. Thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with saturated aqueous sodium hydrogen carbonate, dried overmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(ethyl acetate/methanol=95/5) to obtain 30 mg of the target compound.

¹H-NMR (DMSO-d₆) δ (ppm) 2.33 (s, 3H), 2.72 (m, 4H), 3.13 (m, 4H), 6.53(d, 4H), 7.03 (d, 4H), 9.42 (s, 2H)

Example 30 Synthesis of Compound 52

In a 100 ml three-neck flask, thiohydroquinone (1.6 g) was dissolved inmethanol (15 ml) under nitrogen atmosphere. To this solution was addedan aqueous solution (0.7 ml) of sodium hydroxide (0.51 g),N,N-bis(2-chloroethyl)-2-chloropropionamide (1.0 g) was further added,and the mixture was stirred at 50° C. for 2 hours. To the reactionmixture was added ethyl acetate and diluted hydrochloric acid forseparation. The organic layer was washed with saturated brine, driedover sodium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(ethyl acetate/hexane=3/2). The resulting oil was dissolved in methanol,water was added thereto, and then the precipitates produced werecollected by filtration, and dried under reduced pressure to obtain 1.2g of the target compound.

¹H-NMR (DMSO-d₆) δ (ppm) 2.32 (t, 2H), 2.86 (m, 6H), 3.32 (m, 4H), 6.70(d, 6H), 7.22 (m, 6H), 9.60 (s, 3H)

Example 31 Synthesis of Compound 212

Compound 71 (0.51 g) synthesized in Example 14 and p-toluenesulfonicacid methyl ester (0.41 g) were stirred at 120° C. for 5 hours on an oilbath. To the reaction mixture was added ethyl acetate and acetone, themixture was decanted, then to the residue was added a solution ofpotassium iodide (0.35 g) in acetone-methanol mixed solvent, and themixture was subjected to suction filtration. The residue obtained byconcentrating the filtrate under reduced pressure was purified by silicagel column chromatography (methylene chloride/methanol=9/1-8/2), and theresulting oil was crystallized by treatment with diethyl ether. Thecrystals were collected by filtration, and dried under reduced pressureto obtain 168 mg of the target compound.

¹H-NMR (DMSO-d₆) δ (ppm) 1.00 (t, 3H), 2.97 (s, 3H), 3.0-3.5 (m, 10H),6.80 (d, 4H), 7.32 (d, 4H), 9.80 (s, 2H)

Example 32 Syntheses of Compounds 220 to 223

The title compounds were synthesized by carrying out the esterificationin the same manner as in Example 13.

Example 33 Syntheses of Compound 224 and Compound 225

To a solution of Compound 97 (1.0 g) synthesized in Example 8 in acetone(10 ml) were added maleic acid (0.31 g), and further ethyl acetate. Theresulting precipitates were separated by filtration, washed with ethylacetate, and dried under reduced pressure to obtain 1.25 g of the targetcompound.

¹H-NMR (CD₃OD) δ (ppm) 2.95 (m, 4H), 3.07 (m, 4H), 3.63 (s, 2H), 6.28(s, 2H), 6.76 (d, 4H), 7.27 (d, 4H)

In a similar manner, Compound 225 was obtained by using citric acid.

Example 34 Synthesis of Compound 226

Thiohydroquinone (5.05 g), 28% solution of sodium methoxide (8.2 g) inmethanol, and methanol (30 ml) were mixed under water cooling. To theresulting solution was added a solution of1,4-bis(5-bromopentanoyl)piperazine (8.8 g) in methanol (10 ml), and themixture was stirred at 40° C. for 2 hours. The reaction mixture wascooled to room temperature, and concentrated under reduced pressure. Theresulting residue was dissolved in ethyl acetate (200 ml), and washedwith saturated brine (×2). The precipitates produced were separated byfiltration, and dried under reduced pressure to obtain 9.00 g of thetarget compound.

¹H-NMR (DMSO-d₆) δ (ppm) 1.30-1.60 (m, 12H), 2.27 (t, 4H), 2.74 (t, 4H),3.25-3.46 (m, 8H), 6.72 (d, 4H), 7.18 (d, 4H), 9.53 (s, 2H)

Example 35 Synthesis of Compound 227

Thiohydroquinone (4.0 g) was dissolved in methanol (20 ml). To thissolution was added a 28% solution of sodium methoxide (6.7 g) inmethanol, the mixture was stirred, a solution of1,4-bis(2-chloropropionyl)piperazine (3.8 g) in methanol (20 ml) wasfurther added thereto, and the mixture was refluxed by heating for 4hours. The reaction mixture was cooled to room temperature, dilutedhydrochloric acid was added thereto, and the mixture was extracted withethyl acetate. The organic layer was washed with water, and theresulting precipitates were separated by filtration, and washed withethyl acetate. These crystals were dried under reduced pressure toobtain 6.0 g of the target compound.

¹H-NMR (DMSO-d₆) δ (ppm) 2.60 (t, 4H), 2.96 (t, 4H), 3.28-3.56 (m, 8H),6.76 (d, 4H), 7.23 (d, 4H), 9.62 (s, 2H)

Example 36 Synthesis of Compound 228

The title compound was synthesized in the same manner as in Example 35.

The results of mass spectroscopy (Fast Atom Bombardment MassSpectroscopy, positive, p-Nitrobenzylalcohol) are described below.

TABLE 5 Compound No. Parent peak  45 322  48 338  49 364  50 392  51 422 52 502  53 350  54 364  57 481  58 495  59 365  71 350  72 364  73 360 74 362  75 376  77 361  78 393  79 421  80 449  81 378  82 408  83 407 84 368  85 404  86 447  87 396  88 408  89 418  90 402  91 413  92 428 93 428  94 428  95 380  97 379  98 412  99 413 100 413 101 463 102 366105 430 106 430 107 463 108 461 109 421 110 435 111 433 113 378 114 426116 427 118 400 124 435 125 433 191 485 192 517 193 464 194 436 195 443196 402 197 468 198 424 199 410 200 436 201 396 202 407 203 447 204 485205 453 206 463 207 423 208 467 209 490 210 462 211 457 212 364 213 463214 484 215 484 216 484 217 494 218 483 219 497 220 524 221 767 222 521223 721 224 379 225 379

Text Example 1 Test of Measurement of RNR Inhibitory Activity

(a) Preparation of R1 and R2 subunits of human RNR

Starting from a plasmid p3I containing cDNA coding for R1 subunit ofhuman RNR protein (disclosed in Nucleic Asids Research, 19, p.3741,1991), a DNA was obtained, in which was introduced an Nde I restrictionsite just before the translation initiation site of R1 subunit and a BamHI restriction site just after the translation termination site in sucha manner that the amino acid sequence of R1 subunit was completelyunchanged. The preparation of DNA was carried out by methods ofintroducing mutations and DNA amplification based on the PCR utilizingsynthetic DNA fragments according to the method described in theMolecular Cloning, 2nd Edition. The Nde I/Bam HI restriction fragmentcontaining a region coding for the R1 subunit deriving from the DNA wasinserted between the NdeI and Bam HI sites of plasmid pET3a (Novagen) toconstruct a plasmid pETR1. The plasmid was transformed into Eschelichiacoli BL21(λ DE3)plysS strain (Novagen) to construct a BL21(λDE3)plysSpETR1 strain also according to the method described in theMolecular Cloning, 2nd Edition.

Similarly, a DNA fragment was obtained, from a human cell strain HL60cDNA library through the methods of introducing mutations and DNAamplification based on the PCR utilizing synthetic DNA fragments, whichwas introduced with an Nde I restriction site just before thetranslation initiation site of R² subunit and a Bam HI restriction sitejust after the translation termination site in such a manner that theamino acid sequence of R2 subunit were completely unchanged. The NdeI/Bam HI restriction fragment containing the region coding for the R2subunit deriving from the DNA was inserted between the NdeI and Bam HIsites of plasmid pEt3a (Novagen) to construct a plasmid pETR2. Thisplasmid was transformed into Eschelichia coli BL21(λ DE3)plysS strain(Novagen) also according to the method described in the MolecularCloning, 2nd Edition to construct a BL21(λ DE3)plysSpETR2 strain.

By using one loop, the BL21(λ DE3) plysSpETR1 strain was inoculated to40 ml of Terrific Broth (containing 100 μg/ml of ampicillin and 20 μg/mlof chloramphenicol and free from glycerol, described in MolecularCloning, 2nd Edition) contained in a 300 ml Erlenmeyer flask, andcultured at 28° C. overnight with shaking. 30 ml of the culture brothwas inoculated in 400 ml of the same culture broth contained in a 2liter Erlenmeyer flask, and cultivation was carried out at 16° C. withshaking. Two hours after the start of the cultivation, IPTG was added tothe broth to a final concentration of 0.1 mM, and then the cultivationwas continued for 20 hours. Cells were collected from the culture brothby centrifugation at 7,000× g for 10 minutes at 4° C., and the cellscollected were suspended in 20 ml of Buffer A [50 mM HEPES-NaOH (pH7.6), 1 mM MgCl₂, 1 mM dithiothreitol, 1 mM PMSF] cooled with ice. Thissuspension was sonicated to disrupt the cells, and then centrifuged at12,000×g for 20 minutes at 4° C. The supernatant was collected,streptomycin sulfate was added thereto to a final concentration of 2%(W/V) and the mixture was maintained on ice for 20 minutes, and thencentrifuged at 12,000× g for 20 minutes at 4° C. The supernatant wascollected, an equal volume of 100% saturated aqueous ammonium sulfatewas added thereto with stirring, and then the mixture was maintained onice overnight. Precipitates were collected by centrifugation at 15,000×gfor 20 minutes at 4° C. and dissolved in 2 ml of Buffer A, and then thesolution was subjected to desalting and buffer substitution with BufferA by using PD-10 (Pharmacia Biotech) in a conventional manner.

For all of the subsequent separation and purification steps, FPLC System(Pharmacia Biotech) was used. The desalted fraction was applied toQ-Sepharose FF (Pharmacia Biotech), and separation was carried out underthe following conditions: flow rate: 5.0 ml/minute, separation time: 50minutes, eluent: 0 M to 0.5 M KCl linear gradient in 10 mM potassiumphosphate buffer (pH 7.0). The fractions eluted from 10 minutes to 20minutes were collected and ammonium sulfate was added thereto to a finalconcentration of 0.5 M. The fractions were applied to Phenyl SepharoseHP (Pharmacia Biotech) and eluted at a flow rate of 3.0 ml/minute with10 mM potassium phosphate buffer (pH 7.0)/0.5 M ammonium sulfate for 15minutes, with 10 mM potassium phosphate buffer (pH 7.0) for 15 minutes,and then with 10 mM potassium phosphate buffer (pH 7.0)/0.3% Tween 20for 15 minutes. The fractions eluted in the last 15 minutes werecollected and applied to Resource Q 1 ml (Pharmacia Biotech), washedwith 10 mM potassium phosphate buffer (pH 7.0), and eluted at a flowrate of 1 ml/minute with 10 mM potassium phosphate buffer (pH 7.0)/0.3 MKCl for 10 minutes. The fractions eluted in the first 3 minutes werecollected, and subjected to desalting and buffer substitution withBuffer A by using PD-10 to obtain a purified R1 preparation.

By using one loop, the BL21(λ DE3) plysSpETR² strain was inoculated to40 ml of Terrific Broth (containing 100 μg/ml of ampicillin and 20 μg/mlof chloramphenicol and free from glycerol, described in MolecularCloning, 2nd Edition) in a 300 ml Erlenmeyer flask, and cultured at 28°C. overnight with shaking. 30 ml of the culture broth was inoculated to400 ml of the same culture broth in a 2 liter Erlenmeyer flask, and thenthe cultivation was carried out at 28° C. with shaking. When O.D. (600nm) reached around 0.8, IPTG was added to the broth to a finalconcentration of 1 mM, and the cultivation was continued for 6 hours.Cells were collected from the culture broth by centrifugation at 7,000×gfor 10 minutes at 4° C., and the cells obtained were suspended in 20 mlof Buffer A cooled with ice. This suspension was sonicated to disruptthe cells, and then centrifuged at 12,000×g for 20 minutes at 4° C. Thesupernatant was collected, streptomycin sulfate was added thereto to afinal concentration of 2% (W/V), and the mixture was maintained on icefor 20 minutes, and then centrifuged at 12,000×g for 20 minutes at 4° C.The supernatant was collected, an equal volume of 100% saturated aqueousammonium sulfate was added thereto with stirring, and then the mixturewas maintained on ice overnight. Precipitates were collected bycentrifugation at 15,000× for 20 minutes at 4° C. and dissolved in 2 mlof Buffer A, and then the solution was subjected to desalting and buffersubstitution with Buffer A by using PD-10 (Pharmacia Biotech) in aconventional manner.

For all of the subsequent separation and purification steps, FPLC System(Pharmacia Biotech) was used. The desalted fraction was applied toQ-Sepharose FF (Pharmacia Biotech), and separation was carried out underthe following conditions: flow rate: 5.0 ml/minute, separation time: 50minutes, eluent: 0 M to 0.5 M KCl linear gradient in 10 mM potassiumphosphate buffer (pH 7.0). The fractions eluted from 10 minutes to 25minutes were collected, ammonium sulfate was added thereto to a finalconcentration of 0.5 M, and the mixture was applied to Resource ETH. Thefractions were eluted at a flow rate of 0.5 ml/minute with 10 mMpotassium phosphate buffer (pH 7.0)/0.5 M ammonium sulfate for 15minutes, with 10 mM potassium phosphate buffer (pH 7.0) for 15 minutes,and then with 10 mM potassium phosphate buffer (pH 7.0)/0.3% Tween 20for 15 minutes. The fractions eluted in the last 15 minutes werecollected and applied to Resource Q 1 ml (Pharmacia Biotech), and thenwashed with 10 mM potassium phosphate buffer (pH 7.0)/0.5 M ammoniumsulfate at a flow rate of 1 ml/minute for 10 minutes. The fractions wereeluted with 10 mM potassium phosphate buffer for 10 minutes. Thefractions eluted in the first 3 minutes were collected, and subjected todesalting and buffer substitution with Buffer A by using PD-10 to obtaina purified R² preparation.

(b) In vitro Measurement of Human RNR Inhibitory Activity

By using the above-obtained human RNR subunits, inhibitory activity onthe human RNR was tested in vitro. The composition of the reactionmixture is as follows:

50 mM HEPES-NaOH (pH 7.6)

5 mM MgCl₂

10 mM Dithiothreitol

100 μM CDP

1 mM ATP

40 ng/ml Purified human RNR R1 subunit, and

40 ng/ml Purified human RNR R2 subunit.

The above reaction mixture (25 μl) containing a test compound at anappropriate final concentration was prepared, and the conversion fromCDP to dCDP by RNR was carried out at 37° C. for 30 minutes. Thereaction mixture was subjected to a heat treatment at 95° C. for 5minutes, and centrifuged at 10,000× g for 5 minutes at 4° C. 20 μl ofthe supernatant was collected and 5 μl of 25 mg/ml snake venom (Sigma)was added thereto. Dephosphorylation reaction was carried out at 37° C.for 60 minutes to allow complete conversion of CDP, ATP and dCDP as thereaction product present in the reaction mixture into CR, AR and CdR,respectively. The reaction mixture was subjected to a heat treatment at95° C. for 5 minutes, and centrifuged at 10,000× g for 5 minutes at 4°C. 180 μl of acetonitrile was added to 20 μl of the supernatant, and themixture was centrifuged again at 10,000× g for 5 minutes at 4° C., andthe resulting supernatant was used as a sample for analysis. Theanalysis was performed by high performance liquid chromatography.Analytical conditions are as follows:

Column: Licrospher NH2 (Merck)

Flow rate: 1.5 ml/min

Detection: 270 nm, and

Eluent: acetonitrile/water (90:10, V/V).

CdR in the analyzed sample was identified and its concentration wasdetermined by comparison with elution time and peak area with those ofCdR at known concentration. A concentration of a test compound whichinhibited the RNR activity by 50% under the aforementioned conditionswas calculated by comparing a CdR concentration in a sample, obtainedfrom the reaction without drug treatment, with a CdR concentration in asample obtained from the reaction wherein the test compound at a knownconcentration was added, and the value obtained was determined as IC₅₀.

Test Example 2 Test for Growth Inhibition of Hela S3 Cells

HeLa S3 cells prepared at 1×10⁴ cells/ml in MEM culture mediumcontaining 10% fetal bovine serum and 2 mM glutamine were added to eachwell of a 96-well microtiter plate (0.1 ml for each well). The cellswere cultured at 37° C. in a CO₂ incubator for 24 hours, and then 0.05ml of test compound appropriately diluted with the above medium wasadded to each well, and then the mixture was cultured at 37° C. in a CO₂incubator for 72 hours. After the culture supernatant was removed, eachwell was washed with 0.1 ml of PBS buffer twice, and 0.1 ml of theaforementioned medium was added to each well again.

Cell Proliferation Kit II (Boehringer Mennheim) was used for measurementof cell number in each well. After a coloring reaction reagent wasadded, the plate was warmed to 37° C. in a CO₂ incubator for 3 hours.Then, absorbances at 490 nm and 655 nm were measured by a microplatereader, and a value (difference of absorbance) was calculated for eachwell by subtracting the absorbance at 650 nm from the absorbance at 490nm. By comparing the differences of absorbance for cells withouttreatment and cells treated with a test compound at a knownconcentration, a concentration of test compound which inhibited the cellgrowth by 50% was calculated, and the value obtained was determined asIC₅₀. The values of RNR inhibitory activity obtained in Example 8, andthe values of cell growth inhibitory activity obtained in Example 9 areshown in the following tables (the compound numbers used in the tablescorrespond to the compound numbers shown in the aforementioned tables).

TABLE 6 RNR Inhibition Cell growth inhibition Compound No. (IC₅₀, μM)(IC₅₀, μM) 1 4.26 5.15 7 4.82 >101 8 4.38 6.50 27 0.50 1.53 45 3.64 5.6448 1.73 5.16 49 5.45 16.04 50 3.97 3.81 52 4.38 6.50 53 1.05 1.71 540.48 4.63 55 6.87 7.78 57 0.73 14.44 58 4.76 18.59 59 5.73 5.81 60 2.757.67 61 3.77 13.40 71 1.23 3.94 72 1.19 2.18 73 0.60 1.61 74 0.82 2.0075 1.66 3.56 77 0.06 2.38 78 0.31 1.61 79 1.37 3.06 80 0.74 1.43 81 0.291.23 82 1.42 1.30 83 2.95 5.17 84 2.74 11.99 85 0.61 2.50 86 3.14 3.7887 1.01 2.57 88 1.79 3.22 89 1.46 4.66 90 2.03 6.38 91 1.69 2.72 92 0.892.14 93 0.63 9.04 94 0.46 4.00 95 0.88 3.56 97 0.17 0.88 98 3.36 14.9799 2.79 5.80 100 1.58 4.97 101 5.05 12.88 102 0.69 1.42 103 2.11 1.74104 2.11 1.74 105 3.99 9.07 106 4.64 6.77 107 4.20 24.86 108 0.64 2.64109 2.36 38.89 111 1.85 11.39 113 4.77 3.80 114 3.44 2.74 115 4.14 6.14116 4.13 3.02 117 1.69 2.72 118 6.87 7.78 124 0.09 3.68 125 0.91 4.55131 6.59 127.70 132 3.50 45.55 133 2.27 14.51 134 0.68 2.05 135 0.436.02 136 0.69 9.14 137 0.87 5.45 138 2.29 18.28 152 5.14 17.96 156 2.275.45 158 1.42 12.72 159 0.69 6.89 160 0.95 20.09 161 1.13 34.19 162 1.703.70 163 2.10 5.17 165 3.98 50.14 166 3.09 31.25 171 8.01 30.03 172 2.6419.48 173 3.63 12.93 183 0.42 10.42 184 0.30 2.46 186 11.93 56.03 1901.38 16.86 191 1.36 4.78 192 2.85 4.51 193 N.T. 0.36 194 0.84 11.71 1950.55 3.16 196 1.52 7.08 197 3.24 4.06 198 4.86 4.85 199 3.99 5.14 2004.20 4.13 201 2.49 4.29 202 1.87 42.64 203 3.18 3.45 204 1.50 3.38 2051.19 7.32 206 1.13 3.31 207 0.87 1.71 208 3.46 5.93 209 2.67 3.09 2105.91 2.82 211 3.24 3.04 213 2.06 179.95 214 2.69 7.73 215 3.68 12.72 2163.63 11.54 218 4.97 23.18 219 3.51 25.20 220 5.20 0.29 222 0.43 0.36 2240.42 0.40 225 0.63 0.55 N.T.: Not tested.

Test Example 3 Antineoplastic Effect Against Human Ovary Cancer A2780Cells

2 mm cubes (tumor fragments of 8 mm³) of human ovary cancer A2780 cellswere subcutaneously transplanted to nude mice BALB/cAJcl-nu (CLEA JAPAN)in the abdomens. When the tumor volume reached to from 50 to 300 mm³after the transplantation, the mice were arbitrarily divided into groupseach consisting of 5 mice, and intraperitoneally administered with adrug solution once a day for 5 days. After weighing compounds, the drugsolution was prepared before use by dissolving the drug in 99.5% ethanol(final concentration: 5%, analytical grade, Kanto Kagaku) orN,N-dimethylacetamide (final concentration: 5%, analytical grade, KantoKagaku), adding CREMOPHOR EL (a derivative of caster oil and ethyleneoxide, final concentration: 10%, Sigma Chemical) to the solution, andsuspending the solution in physiological saline (Otsuka PhysiologicalSaline for Injection, Otsuka Pharmaceutical). For evaluation of theeffect, a tumor volume was calculated in accordance with Equation 1, aratio of tumor volume (V) after the administration of drug solution totumor volume (V₀) before the administration of drug solution wascalculation (V/V₀), and the ratio was compared with that for theuntreated group to determine T/C (Equation 2). The results are shown inthe table set out below. In the table, administration dose, T/C andevaluation day are shown. Equation  1: $\begin{matrix}{{{Tumor}\quad {volume}\quad \left( {mm}^{3} \right)} = \quad {{Length}\quad ({mm}) \times {Width}\quad ({mm}) \times}} \\{\quad {{Width}\quad ({mm}) \times 1\text{/}2}}\end{matrix}$ Equation  2: $\begin{matrix}{{T/C} = \quad {\left( {{V/V_{0}}\quad {for}\quad {drug}\text{-}{administered}\quad {group}} \right)/}} \\{\quad \left( {{V/V_{0}}\quad {for}\quad {untreated}\quad {group}} \right)}\end{matrix}$

TABLE 7 Compound Dose Antitumor Evaluation No. mg/kg/day activity T/Cday* 27 500 0.46 7 48 500 0.54 7 72 500 0.50 4 77 500 0.54 4 78 500 0.534 79 500 0.40 4 91 500 0.48 4 94 500 0.53 7 97 500 0.43 7 102 500 0.47 7103 500 0.50 4 193 250 0.46 4 209 500 0.50 7 211 500 0.37 9 177 500 0.544 227 500 0.53 7 *Days after the first administration of test compound

Test Example 4 Antineoplastic Effect Against Human Lung Cancer Lu-65Cells

2 mm cubes (tumor fragments of 8 mm³) of human lung cancer Lu-65 cellswere subcutaneously transplanted to nude mice BALB/cAJcl-nu (CLEA JAPAN)on their abdomens. When the tumor volume reached to from 50 to 300 mm³after the transplantation, the mice were arbitrarily divided into groupseach consisting of 5 mice, and intraperitoneally administered with adrug solution twice a day for 5 days. After weighing compounds, the drugsolution was prepared before use by dissolving the drug in 99.5% ethanol(final concentration: 5%, analytical grade, Kanto Kagaku), addingCREMOPHOR EL (a derivative of caster oil and ethylene oxide, finalconcentration: 10%, Sigma Chemical) to the solution, and suspending thesolution in physiological saline (Otsuka Physiological Saline forInjection, Otsuka Pharmaceutical). For evaluation of the effect, a tumorvolume was calculated in accordance with Equation 1, a ratio of tumorvolume (V) after the administration of drug solution to tumor volume(V₀) before the administration of drug solution was calculated (V/V₀),and the ratio was compared with that for the untreated group todetermine T/C (Equation 2). The results are shown in the table set outbelow. Equation  1: $\begin{matrix}{{{Tumor}\quad {volume}\quad \left( {mm}^{3} \right)} = \quad {{Length}\quad ({mm}) \times {Width}\quad ({mm}) \times}} \\{\quad {{Width}\quad ({mm}) \times 1\text{/}2}}\end{matrix}$ Equation  2: $\begin{matrix}{{T/C} = \quad {\left( {{V/V_{0}}\quad {for}\quad {drug}\text{-}{administered}\quad {group}} \right)/}} \\{\quad \left( {{V/V_{0}}\quad {for}\quad {untreated}\quad {group}} \right)}\end{matrix}$

TABLE 8 Compound Dose Antitumor Evaluation No. mg/kg/day activity T/Cday* 27 1000 (500 × 2) 0.25 7 *Days after the first administration oftest compound

INDUSTRIAL AVAILABILITY

The compounds of the aforementioned formula (I) or (II), which are theactive ingredient of the medicament of the present invention, caninhibit ribonucleotide reductase, and selectively inhibit proliferationof cancer cells. Therefore, the medicament of the present invention isuseful, for example, as an agent for cancer treatment. The novelcompounds represented by the aforementioned formula (XII) provided bythe present invention are useful as active ingredients of medicamentssuch as medicaments for cancer treatment.

What is claimed is:
 1. A method for inhibiting ribonucleotide reductasecomprising administering to a subject in need thereof an effectiveamount of a compound represented by formula (I), or a physiologicallyacceptable salt thereof: Ar¹—S—R¹—S—Ar²  (I) wherein R¹ represents anonmetal bridging group selected from —C₂H₄—S—C₂H₄—, —C₂H₄—S—C₃H₆—,—C₂H₄—S—C₄H₄—, —C₂H₄—S—C₄H₆—, —C₂H₄S—C₄H₈—, —C₃H₆—S—C₃H₆—,—C₃H₆—S—C₄H₆—, —C₃H₆—S—C₄H₈—, —C₄H₈—S—C₄H₈—, —CH₂CO—S—C₂H₄—,—CH₂CO—S—C₃H₆—, —CH₂CO—S—C₄H₈—, —CH₂CO—S—C₄H₆—, —CH₂CO—S—C₄H₄—,—CH(CH₃)CO—S—C₂H₄—, —C₂H₄CO—S—CH₂CH(OH)CH₂—, —CH₂CO—S—C₂H₄NHCOCH₂—,—C₂H₄CO—S—C₂H₄NHCOC₂H₄—, —C₂H₄O—C₂H₄—, —C₂H₄—O—C₃H₆—, —C₂H₄—O—C₄H₄—,—C₂H₄—O—C₄H₆—, —C₂H₄—O—C₄H₈—, —C₃H₆—O—C₃H₆—, —C₃H₆—O—C₄H₆—,—C₃H₆—O—C₄H₈—, —C₄H₈—O—C₄H₈—, —CH₂CO—O—C₂H₄—, —CH₂CO—O—C₃H₆—,—CH₂CO—O—C₄H₈—, —CH₂CO—O—C₄H₆—, —CH₂CO—O—C₄H₄—, —CH(CH₃)CO—O—C₂H₄—,—C₂H₄CO—O—CH₂CH(OH)CH₂—, —CH₂CO—O—C₂H₄NHCOCH₂—, —C₂H₄CO—O—C₂H₄NHCOC₂H₄—;—R²—N(R⁴)—R³—, wherein R², R³ and R⁴ are defined as follows: R² R³ R⁴—C₂H₄— —C₂H₄— —H— —C₃H₆— —C₃H₆— —H— —C₄H₈— —C₄H₈— —H— —C₂H₄— —C₂H₄— —OH——C₂H₄— —C₂H₄— —C(═NH)NH₂ —C₂H₄— —C₂H₄— —COC₃H₇ —C₂H₄— —C₂H₄——COCH₂CH₂CO₂H —C₂H₄— —C₂H₄— —COCH₂CH₂S—Ph—OH-p —C₂H₄— —C₂H₄— —CHO —C₂H₄——C₂H₄— —COCH₃ —C₂H₄— —C₂H₄— —SO₂CH₃ —C₃H₆— —C₃H₆— —CHO —C₂H₄— —C₂H₄——CH₂CH₂NH₂ —CH₂CO— —C₂H₄— —H —CH₂CO— —C₃H₆— —H —CH₂CO— —C₄H₈— —H —CH₂CO——C₄H₆— —H —CH₂CO— —C₄H₄— —H —CH₂CO— —C₄H₄— —CHO —CH(CH₃)CO— —C₂H₄— —H—CH(CH₃)CO— —C₂H₄— —C₂H₄OH —C₂H₄CO— —CH₂CH(OH)CH₂— —C₂H₄OH —CH₂CO——C₂H₄NHCOCH₂— —H —C₂H₄CO— —C₂H₄NHCOC₂H₄— —H —C₂H₄— —C₂H₄— —C₂H₅ —C₂H₄——C₂H₄— —C₃H₇ —C₂H₄— —C₂H₄— —CH₂—C≡CH —C₂H₄— —C₂H₄— —CH₂—CH═CH₂ —C₂H₄——C₂H₄— —CH₂-cyclopropyl —C₂H₄— —C₂H₄— —CH₂—SO₂NH₂ —C₂H₄— —C₂H₄— —CH₂—CN—C₂H₄— —C₂H₄— —C₂H₄—CO—NH₂ —C₂H₄— —C₂H₄— —C₂H₄CO—N(CH₃)₂ —C₂H₄— —C₂H₄——C₂H₄CO—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —CH₂—CO—CH₃ —C₂H₄— —C₂H₄— —C₂H₄—NH—CO—NH₂—C₂H₄— —C₂H₄— —C₂H₄—NH—CO—CH₃ —C₂H₄— —C₂H₄— —CH₂F —C₂H₄— —C₂H₄— —CF₃—C₂H₄— —C₂H₄— —C₂H₄-(N-succinimido) —C₂H₄— —C₂H₄— —C₂H₄—S—CH₃ —C₂H₄——C₂H₄— —CH₂-ethyleneacetal —C₂H₄— —C₂H₄— —CH₂-(2-thienyl) —C₂H₄— —C₂H₄—-furfuryl —C₂H₄— —C₂H₄— —CH₂-(4-pyridyl) —C₂H₄— —C₂H₄— -o-hydroxybenzyl—C₂H₄— —C₂H₄— -m-hydroxybenzyl —C₂H₄— —C₂H₄— -p-hydroxybenzyl —C₂H₄——C₂H₄— —(CH₂)₃—OH —C₂H₄— —C₂H₄— —CH₂—NH—CO—CH₃ —C₂H₄— —C₂H₄— —CH₂—CO—NH₂—C₂H₄— —C₂H₄— -benzyl —C₂H₄— —C₂H₄— —CH₂-(3-pyridyl) —C₂H₄— —C₂H₄——CH₂-(2-pyridyl) —C₂H₄— —C₂H₄— —CH₂-(2-quinolinyl) —C₂H₄— —C₂H₄——C₂H₄—OH —C₂H₄— —C₂H₄— —(CH₂)₃—OCH₃ —C₂H₄— —C₂H₄— —C₂H₄—OCH₃ —C₂H₄——C₂H₄— -o-fluorobenzyl —C₂H₄— —C₂H₄— -p-fluorobenzyl —C₂H₄— —C₂H₄——C₂H₄—CO-(N-morpholino) —C₂H₄— —C₂H₄— —C₂H₄—CO-(1-piperidyl) —C₂H₄——C₂H₄— —C₂H₄—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —C₂H₄-(N-morpholino) —C₂H₄— —C₂H₄——C₂H₄-(1-piperidyl) —C₂H₄— —C₂H₄— —CO—CH₃ —C₂H₄— —C₂H₄— —CO—C₂H₅ —C₂H₄——C₂H₄— —CO—C₆H₅ —C₂H₄— —C₂H₄— —CO-(2-pyridyl) —C₂H₄— —C₂H₄——CO-(3-pyridyl) —C₂H₄— —C₂H₄— —CO-(4-pyridyl) —C₂H₄— —C₂H₄— —SO₂—CH₃—C₂H₄— —C₂H₄— —SO₂—C₆H₅ —C₂H₄— —C₂H₄— —CO—NH₂ —C₂H₄— —C₂H₄— —CO—NH(CH₃)—C₂H₄— —C₂H₄— —CO—N(CH₃)₂ —C₂H₄— —C₂H₄— —CO—N(C₂H₅)₂ —C₂H₄— —C₂H₄——CO-(N-morpholino) —C₂H₄— —C₂H₄— —CO-(1-piperidyl) —C₂H₄— —C₂H₄——CO—NH—C₆H₅ —C₂H₄— —C₂H₄— —CO—NH-(2-pyridyl) —C₂H₄— —C₂H₄— —SO₂—NH₂—C₂H₄— —C₂H₄— —SO₂—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —SO₂-(N-morpholino);

—CH₂—, —C₂H₄—, —C₃H₆—, —C₄H₈—, —C₅H₁₀—, —C₆H₁₂—, —C₇H₁₄—, —C₈H₁₆—,—C₉H₁₈—, —C₁₀H₂₀—, —C₁₁H₂₂, —C₂H₄—SO₂—C₂H₄—SO₂—C₂H₄—, —CH(CH₃),—CH(C₂H₅)—, CH(n—C₃H₇)—, —CH(C₆H₅)—, —C(CH₃)₂—, —CH(COOH)—, CH(C₂H₄OH)—,—CH(CH₃)—CH₂—, —CH(C₂H₄OH)—CH₂—, —CH(COOH)—CH₂—, —CH(C₂H₅)—CH₂—,—CH₂—CH(OH)—CH₂—, —CH₂—C(CH₂B)₂—CH₂, wherein B is p-hydroxyphenylthio,CH₂—S—CH₂—, —CH₂—CH═CH—CH₂—, —CH₂—C≡C—CH₂—, —CH₂—C₆H₄—CH₂— wherein—C₆H₄—, is an o-phenylene group, —C₂H₄—O—CH₂—O—C₂H₄—,—C₂H₄—O—C₂H₄—O—C₂H₄—, —CH₂—COO—C₂H₄—OCOCH₂—, —CH₂—COO—C₃H₆—OCOCH₂—,—CH₂CH(OH)CH₂—O—C₂H₄—O—CH₂CH(OH)CH₂—, —(C₂H₄O)₂—CO—CH₂—CO—(C₂H₄O)₂,—(C₂H₄O)₂—CO—(trans)CH═CH—CO—(C₂H₄O)₂—, —CH₂—COO—(C₂H₄O)₃—CO—CH₂—,—CH₂—COO—(C₂H₄O)₄—CO—CH₂—, —(C₂H₄O)₃—C₂H₄—, —(C₂H₄O)₄—C₂H₄—,—(C₂H₄O)₅—C₂H₄—, —(C₂H₄O)₃—CO—(C₂H₄O)₃—, —(C₂H₄O)₂—CO—C₂H₄—CO—(C₂H₄O)₂,—CH₂—CO—CO—CH₂—, —CO—CH₂—CO—,

and Ar¹ and Ar² each represents a nonsubstituted 4-hydroxyphenyl group.2. The method according to claim 1 wherein the compound of formula (I)is the active ingredient in a pharmaceutical composition comprising saidcompound and a pharmaceutically acceptable carrier or diluent.
 3. Amethod for selectively inhibiting cancer cell proliferation byinhibiting ribonucleotide reductase comprising administering to asubject in need thereof an effective amount of a compound represented byformula (I), or a physiologically acceptable salt thereof:Ar¹—S—R¹—S—Ar²  (I) wherein R¹ represents a nonmetal bridging groupselected from —C₂H₄—S—C₂H₄—, —C₂H₄—S—C₃H₆—, —C₂H₄—S—C₄H₄—,—C₂H₄—S—C₄H₆—, —C₂H₄S—C₄H₈—, —C₃H₆—S—C₃H₆—, —C₃H₆—S—C₄H₆—,—C₃H₆—S—C₄H₈—, —C₄H₈—S—C₄H₈—, —CH₂CO—S—C₂H₄—, —CH₂CO—S—C₃H₆—,—CH₂CO—S—C₄H₈—, —CH₂CO—S—C₄H₆—, —CH₂CO—S—C₄H₄—, —CH(CH₃)CO—S—C₂H4—,—C₂H₄CO—S—CH₂CH(OH)CH₂—, —CH₂CO—S—C₂H₄NHCOCH₂—, —C₂H₄CO—S—C₂H₄NHCOC₂H₄—,—C₂H₄O—C₂H₄—, —C₂H₄—O—C₃H₆—, —C₂H₄—O—C₄H₄—, —C₂H₄—O—C₄H₆—,—C₂H₄—O—C₄H₈—, —C₃H₆—O—C₃H₆—, —C₃H₆—O—C₄H₆—, —C₃H₆—O—C₄H₈—,—C₄H₈—O—C₄H₈—, —CH₂CO—O—C₂H₄—, —CH₂CO—O—C₃H₆—, —CH₂CO—O—C₄H₈—,—CH₂CO—O—C₄H₆—, —CH₂CO—O—C₄H₄—, —CH(CH₃)CO—O—C₂H₄—,—C₂H₄CO—O—CH₂CH(OH)CH₂—, —CH₂CO—O—C₂H₄NHCOCH₂, —C₂H₄CO—O—C₂H₄NHCOC₂H₄—;—R²—N(R⁴)—R³—, wherein R², R³ and R⁴ are defined as follows: R² R³ R⁴—C₂H₄— —C₂H₄— —H— —C₃H₆— —C₃H₆— —H— —C₄H₈— —C₄H₈— —H— —C₂H₄— —C₂H₄— —OH——C₂H₄— —C₂H₄— —C(═NH)NH₂ —C₂H₄— —C₂H₄— —COC₃H₇ —C₂H₄— —C₂H₄——COCH₂CH₂CO₂H —C₂H₄— —C₂H₄— —COCH₂CH₂S—Ph—OH-p —C₂H₄— —C₂H₄— —CHO —C₂H₄——C₂H₄— —COCH₃ —C₂H₄— —C₂H₄— —SO₂CH₃ —C₃H₆— —C₃H₆— —CHO —C₂H₄— —C₂H₄——CH₂CH₂NH₂ —CH₂CO— —C₂H₄— —H —CH₂CO— —C₃H₆— —H —CH₂CO— —C₄H₈— —H —CH₂CO——C₄H₆— —H —CH₂CO— —C₄H₄— —H —CH₂CO— —C₄H₄— —CHO —CH(CH₃)CO— —C₂H₄— —H—CH(CH₃)CO— —C₂H₄— —C₂H₄OH —C₂H₄CO— —CH₂CH(OH)CH₂— —C₂H₄OH —CH₂CO——C₂H₄NHCOCH₂— —H —C₂H₄CO— —C₂H₄NHCOC₂H₄— —H —C₂H₄— —C₂H₄— —C₂H₅ —C₂H₄——C₂H₄— —C₃H₇ —C₂H₄— —C₂H₄— —CH₂—C≡CH —C₂H₄— —C₂H₄— —CH₂—CH═CH₂ —C₂H₄——C₂H₄— —CH₂-cyclopropyl —C₂H₄— —C₂H₄— —CH₂—SO₂NH₂ —C₂H₄— —C₂H₄— —CH₂—CN—C₂H₄— —C₂H₄— —C₂H₄—CO—NH₂ —C₂H₄— —C₂H₄— —C₂H₄CO—N(CH₃)₂ —C₂H₄— —C₂H₄——C₂H₄CO—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —CH₂—CO—CH₃ —C₂H₄— —C₂H₄— —C₂H₄—NH—CO—NH₂—C₂H₄— —C₂H₄— —C₂H₄—NH—CO—CH₃ —C₂H₄— —C₂H₄— —CH₂F —C₂H₄— —C₂H₄— —CF₃—C₂H₄— —C₂H₄— —C₂H₄-(N-succinimido) —C₂H₄— —C₂H₄— —C₂H₄—S—CH₃ —C₂H₄——C₂H₄— —CH₂-ethyleneacetal —C₂H₄— —C₂H₄— —CH₂-(2-thienyl) —C₂H₄— —C₂H₄—-furfuryl —C₂H₄— —C₂H₄— —CH₂-(4-pyridyl) —C₂H₄— —C₂H₄— -o-hydroxybenzyl—C₂H₄— —C₂H₄— -m-hydroxybenzyl —C₂H₄— —C₂H₄— -p-hydroxybenzyl —C₂H₄——C₂H₄— —(CH₂)₃—OH —C₂H₄— —C₂H₄— —CH₂—NH—CO—CH₃ —C₂H₄— —C₂H₄— —CH₂—CO—NH₂—C₂H₄— —C₂H₄— -benzyl —C₂H₄— —C₂H₄— —CH₂-(3-pyridyl) —C₂H₄— —C₂H₄——CH₂-(2-pyridyl) —C₂H₄— —C₂H₄— —CH₂-(2-quinolinyl) —C₂H₄— —C₂H₄——C₂H₄—OH —C₂H₄— —C₂H₄— —(CH₂)₃—OCH₃ —C₂H₄— —C₂H₄— —C₂H₄—OCH₃ —C₂H₄——C₂H₄— -o-fluorobenzyl —C₂H₄— —C₂H₄— -p-fluorobenzyl —C₂H₄— —C₂H₄——C₂H₄—CO-(N-morpholino) —C₂H₄— —C₂H₄— —C₂H₄—CO-(1-piperidyl) —C₂H₄——C₂H₄— —C₂H₄—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —C₂H₄-(N-morpholino) —C₂H₄— —C₂H₄——C₂H₄-(1-piperidyl) —C₂H₄— —C₂H₄— —CO—CH₃ —C₂H₄— —C₂H₄— —CO—C₂H₅ —C₂H₄——C₂H₄— —CO—C₆H₅ —C₂H₄— —C₂H₄— —CO-(2-pyridyl) —C₂H₄— —C₂H₄——CO-(3-pyridyl) —C₂H₄— —C₂H₄— —CO-(4-pyridyl) —C₂H₄— —C₂H₄— —SO₂—CH₃—C₂H₄— —C₂H₄— —SO₂—C₆H₅ —C₂H₄— —C₂H₄— —CO—NH₂ —C₂H₄— —C₂H₄— —CO—NH(CH₃)—C₂H₄— —C₂H₄— —CO—N(CH₃)₂ —C₂H₄— —C₂H₄— —CO—N(C₂H₅)₂ —C₂H₄— —C₂H₄——CO-(N-morpholino) —C₂H₄— —C₂H₄— —CO-(1-piperidyl) —C₂H₄— —C₂H₄——CO—NH—C₆H₅ —C₂H₄— —C₂H₄— —CO—NH-(2-pyridyl) —C₂H₄— —C₂H₄— —SO₂—NH₂—C₂H₄— —C₂H₄— —SO₂—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —SO₂-(N-morpholino);

—CH₂—, —C₂H₄—, —C₃H₆—, —C₄H₈—, —C₅H₁₀—, —C₆H₁₂—, —C₇H₁₄—, —C₈H₁₆—,—C₉H₁₈—, —C₁₀H₂₀—, —C₁₁H₂₂, —C₂H₄—SO₂—C₂H₄—SO₂—C₂H₄—, —CH(CH₃),—CH(C₂H₅)—, CH(n—C₃H₇)—, —CH(C₆H₅)—, —C(CH₃)₂—, —CH(COOH)—, CH(C₂H₄OH)—,—CH(CH₃)—CH₂—, —CH(C₂H₄OH)—CH₂—, —CH(COOH)—CH₂—, —CH(C₂H₅)—CH₂—,—CH₂—CH(OH)—CH₂—, —CH₂—C(CH₂B)₂—CH₂, wherein B is p-hydroxyphenylthio,CH₂—S—CH₂—, —CH₂—CH═CH—CH₂—, —CH₂—C≡C—CH₂—, —CH₂—C₆H₄—CH₂— wherein—C₆H₄—, is an o-phenylene group, —C₂H₄—O—CH₂—O—C₂H₄—,—C₂H₄—O—C₂H₄—O—C₂H₄—, —CH₂—COO—C₂H₄—OCOCH₂—, —CH₂—COO—C₃H₆—OCOCH₂—,—CH₂CH(OH)CH₂—O—C₂H₄—O—CH₂CH(OH)CH₂—, —(C₂H₄O)₂—CO—CH₂—CO—(C₂H₄O)₂,—(C₂H₄O)₂—CO—(trans)CH═CH—CO—(C₂H₄O)₂—, —CH₂—COO—(C₂H₄O)₃—CO—CH₂—,—CH₂—COO—(C₂H₄O)₄—CO—CH₂—, —(C₂H₄O)₃—C₂H₄—, —(C₂H₄O)₄—C₂H₄—,—(C₂H₄O)₅—C₂H₄—, —(C₂H₄O)₃—CO—(C₂H₄O)₃—, —(C₂H₄O)₂—CO—C₂H₄—CO—(C₂H₄O)₂,—CH₂—CO—CO—CH₂—, —CO—CH₂—CO—,

and Ar¹ and Ar² each represents a nonsubstituted 4-hydroxyphenyl group.4. A method for treatment of ovarian or lung cancer comprisingadministering to a subject in need of treatment an effective amount of acompound represented by formula (I), or a physiologically acceptablesalt thereof: Ar¹—S—R¹—S—Ar²  (I) wherein R¹ represents a nonmetalbridging group selected from —C₂H₄—S—C₂H₄—, —C₂H₄—S—C₃H₆—,—C₂H₄—S—C₄H₄—, —C₂H₄—S—C₄H₆—, —C₂H₄S—C₄H₈—, —C₃H₆—S—C₃H₆—,—C₃H₆—S—C₄H₆—, —C₃H₆—S—C₄H₈—, —C₄H₈—S—C₄H₈—, —CH₂CO—S—C₂H₄—,—CH₂CO—S—C₃H₆—, —CH₂CO—S—C₄H₈—, —CH₂CO—S—C₄H₆—, —CH₂CO—S—C₄H₄—,—CH(CH₃)CO—S—C₂H4—, —C₂H₄CO—S—CH₂CH(OH)CH₂—, —CH₂CO—S—C₂H₄NHCOCH₂—,—C₂H₄CO—S—C₂H₄NHCOC₂H₄—, —C₂H₄O—C₂H₄—, —C₂H₄—O—C₃H₆—, —C₂H₄—O—C₄H₄—,—C₂H₄—O—C₄H₆—, —C₂H₄—O—C₄H₈—, —C₃H₆—O—C₃H₆—, —C₃H₆—O—C₄H₆—,—C₃H₆—O—C₄H₈—, —C₄H₈—O—C₄H₈—, —CH₂CO—O—C₂H₄—, —CH₂CO—O—C₃H₆—,—CH₂CO—O—C₄H₈—, —CH₂CO—O—C₄H₆—, —CH₂CO—O—C₄H₄—, —CH(CH₃)CO—O—C₂H₄—,—C₂H₄CO—O—CH₂CH(OH)CH₂—, —CH₂CO—O—C₂H₄NHCOCH₂, —C₂H₄CO—O—C₂H₄NHCOC₂H₄—;—R²—N(R⁴)—R³—, wherein R², R³ and R⁴ are defined as follows: R² R³ R⁴—C₂H₄— —C₂H₄— —H— —C₃H₆— —C₃H₆— —H— —C₄H₈— —C₄H₈— —H— —C₂H₄— —C₂H₄— —OH——C₂H₄— —C₂H₄— —C(═NH)NH₂ —C₂H₄— —C₂H₄— —COC₃H₇ —C₂H₄— —C₂H₄——COCH₂CH₂CO₂H —C₂H₄— —C₂H₄— —COCH₂CH₂S—Ph—OH-p —C₂H₄— —C₂H₄— —CHO —C₂H₄——C₂H₄— —COCH₃ —C₂H₄— —C₂H₄— —SO₂CH₃ —C₃H₆— —C₃H₆— —CHO —C₂H₄— —C₂H₄——CH₂CH₂NH₂ —CH₂CO— —C₂H₄— —H —CH₂CO— —C₃H₆— —H —CH₂CO— —C₄H₈— —H —CH₂CO——C₄H₆— —H —CH₂CO— —C₄H₄— —H —CH₂CO— —C₄H₄— —CHO —CH(CH₃)CO— —C₂H₄— —H—CH(CH₃)CO— —C₂H₄— —C₂H₄OH —C₂H₄CO— —CH₂CH(OH)CH₂— —C₂H₄OH —CH₂CO——C₂H₄NHCOCH₂— —H —C₂H₄CO— —C₂H₄NHCOC₂H₄— —H —C₂H₄— —C₂H₄— —C₂H₅ —C₂H₄——C₂H₄— —C₃H₇ —C₂H₄— —C₂H₄— —CH₂—C≡CH —C₂H₄— —C₂H₄— —CH₂—CH═CH₂ —C₂H₄——C₂H₄— —CH₂-cyclopropyl —C₂H₄— —C₂H₄— —CH₂—SO₂NH₂ —C₂H₄— —C₂H₄— —CH₂—CN—C₂H₄— —C₂H₄— —C₂H₄—CO—NH₂ —C₂H₄— —C₂H₄— —C₂H₄CO—N(CH₃)₂ —C₂H₄— —C₂H₄——C₂H₄CO—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —CH₂—CO—CH₃ —C₂H₄— —C₂H₄— —C₂H₄—NH—CO—NH₂—C₂H₄— —C₂H₄— —C₂H₄—NH—CO—CH₃ —C₂H₄— —C₂H₄— —CH₂F —C₂H₄— —C₂H₄— —CF₃—C₂H₄— —C₂H₄— —C₂H₄-(N-succinimido) —C₂H₄— —C₂H₄— —C₂H₄—S—CH₃ —C₂H₄——C₂H₄— —CH₂-ethyleneacetal —C₂H₄— —C₂H₄— —CH₂-(2-thienyl) —C₂H₄— —C₂H₄—-furfuryl —C₂H₄— —C₂H₄— —CH₂-(4-pyridyl) —C₂H₄— —C₂H₄— -o-hydroxybenzyl—C₂H₄— —C₂H₄— -m-hydroxybenzyl —C₂H₄— —C₂H₄— -p-hydroxybenzyl —C₂H₄——C₂H₄— —(CH₂)₃—OH —C₂H₄— —C₂H₄— —CH₂—NH—CO—CH₃ —C₂H₄— —C₂H₄— —CH₂—CO—NH₂—C₂H₄— —C₂H₄— -benzyl —C₂H₄— —C₂H₄— —CH₂-(3-pyridyl) —C₂H₄— —C₂H₄——CH₂-(2-pyridyl) —C₂H₄— —C₂H₄— —CH₂-(2-quinolinyl) —C₂H₄— —C₂H₄——C₂H₄—OH —C₂H₄— —C₂H₄— —(CH₂)₃—OCH₃ —C₂H₄— —C₂H₄— —C₂H₄—OCH₃ —C₂H₄——C₂H₄— -o-fluorobenzyl —C₂H₄— —C₂H₄— -p-fluorobenzyl —C₂H₄— —C₂H₄——C₂H₄—CO-(N-morpholino) —C₂H₄— —C₂H₄— —C₂H₄—CO-(1-piperidyl) —C₂H₄——C₂H₄— —C₂H₄—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —C₂H₄-(N-morpholino) —C₂H₄— —C₂H₄——C₂H₄-(1-piperidyl) —C₂H₄— —C₂H₄— —CO—CH₃ —C₂H₄— —C₂H₄— —CO—C₂H₅ —C₂H₄——C₂H₄— —CO—C₆H₅ —C₂H₄— —C₂H₄— —CO-(2-pyridyl) —C₂H₄— —C₂H₄——CO-(3-pyridyl) —C₂H₄— —C₂H₄— —CO-(4-pyridyl) —C₂H₄— —C₂H₄— —SO₂—CH₃—C₂H₄— —C₂H₄— —SO₂—C₆H₅ —C₂H₄— —C₂H₄— —CO—NH₂ —C₂H₄— —C₂H₄— —CO—NH(CH₃)—C₂H₄— —C₂H₄— —CO—N(CH₃)₂ —C₂H₄— —C₂H₄— —CO—N(C₂H₅)₂ —C₂H₄— —C₂H₄——CO-(N-morpholino) —C₂H₄— —C₂H₄— —CO-(1-piperidyl) —C₂H₄— —C₂H₄——CO—NH—C₆H₅ —C₂H₄— —C₂H₄— —CO—NH-(2-pyridyl) —C₂H₄— —C₂H₄— —SO₂—NH₂—C₂H₄— —C₂H₄— —SO₂—N(C₂H₅)₂ —C₂H₄— —C₂H₄— —SO₂-(N-morpholino);

—CH₂—, —C₂H₄—, —C₃H₆—, —C₄H₈—, —C₅H₁₀—, —C₆H₁₂—, —C₇H₁₄—, —C₈H₁₆—,—C₉H₁₈—, —C₁₀H₂₀—, —C₁₁H₂₂, —C₂H₄—SO₂—C₂H₄—SO₂—C₂H₄—, —CH(CH₃),—CH(C₂H₅)—, CH(n—C₃H₇)—, —CH(C₆H₅)—, —C(CH₃)₂—, —CH(COOH)—, CH(C₂H₄OH)—,—CH(CH₃)—CH₂—, —CH(C₂H₄OH)—CH₂—, —CH(COOH)—CH₂—, —CH(C₂H₅)—CH₂—,—CH₂—CH(OH)—CH₂—, —CH₂—C(CH₂B)₂—CH₂, wherein B is p-hydroxyphenylthio,CH₂—S—CH₂—, —CH₂—CH═CH—CH₂—, —CH₂—C≡C—CH₂—, —CH₂—C₆H₄—CH₂— wherein—C₆H₄—, is an o-phenylene group, —C₂H₄—O—CH₂—O—C₂H₄—,—C₂H₄—O—C₂H₄—O—C₂H₄—, —CH₂—COO—C₂H₄—OCOCH₂—, —CH₂—COO—C₃H₆—OCOCH₂—,—CH₂CH(OH)CH₂—O—C₂H₄—O—CH₂CH(OH)CH₂—, —(C₂H₄O)₂—CO—CH₂—CO—(C₂H₄O)₂,—(C₂H₄O)₂—CO—(trans)CH═CH—CO—(C₂H₄O)₂—, —CH₂—COO—(C₂H₄O)₃—CO—CH₂—,—CH₂—COO—(C₂H₄O)₄—CO—CH₂—, —(C₂H₄O)₃—C₂H₄—, —(C₂H₄O)₄—C₂H₄—,—(C₂H₄O)₅—C₂H₄—, —(C₂H₄O)₃—CO—(C₂H₄O)₃—, —(C₂H₄O)₂—CO—C₂H₄—CO—(C₂H₄O)₂,—CH₂—CO—CO—CH₂—, —CO—CH₂—CO—,

and Ar¹ and Ar² each represents a nonsubstituted 4-hydroxyphenyl group.